Positive allosteric modulators of muscarinic m2 receptor

ABSTRACT

The present application relates to positive allosteric modulators of the muscarinic M2 receptor, especially to novel 7-substituted 1-arylnaphthyridine-3-carboxamides, to processes for preparation thereof, to the use thereof, alone or in combinations, for treatment and/or prevention of diseases, and to the use thereof for production of medicaments for treatment and/or prevention of diseases, in particular for treatment and/or prevention of cardiovascular disorders and/or renal disorders.

The present application relates to positive allosteric modulators of themuscarinic M2 receptor, especially to novel 7-substituted1-arylnaphthyridine-3-carboxamides, to processes for preparationthereof, to the use thereof, alone or in combinations, for treatmentand/or prevention of diseases, and to the use thereof for production ofmedicaments for treatment and/or prevention of diseases, in particularfor treatment and/or prevention of cardiovascular disorders and/or renaldisorders.

Muscarinergic receptors are receptors which are positioned on themembrane and, as endogenous ligands, can bind the acetylcholine (ACh)neurotransmitter (acetylcholine receptors), but also be activated bymuscarine. There are five subtypes of these G protein-coupled receptors(M1-M5) which are expressed in almost all kinds of tissue in the humanorganism. They are encountered both in the central and in the peripheralnervous system, and in many organs of the vegetative nervous system.

The M2 type (M2R) is expressed predominantly in the heart. At thecellular level, M2R stimulation by the acetylcholine agonist bringsabout inhibition of adenylcyclase and activation of the inwardlyrectifying potassium channel (IKACh channel, GIRK (G protein activatedinwardly rectifying K+ channel; also Kir3.x). This increases potassiumconductivity, which leads to hyperpolarization of the muscle cells.Accordingly, the cells become more difficult to depolarize, which leadsto an adverse chronotropic and dromotropic effect, and so the heart ratedrops. M2R is the main mediator of the parasympathetic control of heartfunction, which is controlled by the vagus nerve. The right vagus nervereduces the heart rate via the sinus node; the left vagus nervepredominantly increases the atrioventricular conduction time via theatrioventricular node (AV node). Overall, the influence of the vagusnerve on the resting heart rate is predominant compared to thesympathetic nerve. The effects of stimulation of M2R are thus opposed tothose of beta-adrenergic stimulation.

The activation of the M2 receptor by the endogenous acetylcholineagonist, but also by synthetic analogues such as carbachol,oxotremorin-M or iperoxo (Schrage et al., Biochem. Pharmacol. 2014,90(3), 307-319), is effected by binding of the agonist to what is calledthe orthosteric binding site of the receptor and a resultant change inconformation of the receptor or stabilization of the active receptorconfirmation. The conventional naturally occurring muscarine receptoragonists include, as well as the endogenous acetylcholine (ACh) agonist,various plant alkaloids such as arecoline, muscarine, and alsopilocarpine (Neubig et al., Pharmacol Rev., 2003, 55, 597-606). Theorthosteric binding site of all muscarinic acetylcholine receptors ishighly evolutionarily conserved and has a high sequence and structuralhomology between the various subtypes. Therefore, many of the knownagonists are unselective with respect to the various subtypes of themuscarinic acetylcholine receptors (Kruse et al., Mol Pharmacol., 2013,84(4), 528-540). M2R has, as well as an orthosteric binding site, anallosteric binding site as well (Gregory et al., CurrentNeuropharmacol., 2007, 5(3), 157-167). The oldest known allostericmodulator is gallamine (Clark and Mitchelson, Br. J. Pharmac., 1976, 58,323-331).

Allosteric modulators have distinct differences from conventionalorthosteric ligands. The allosteric modulator itself has no directinfluence on receptor activation. The allosteric binding instead resultsin modulation of the binding affinity and/or effectiveness of theorthosteric agonist. The effect of an allosteric modulator can thus bedisplayed only in the presence of the endogenous ligand. This results inspecificity in terms of space and time in the allosteric effect (Conn etal., Nat. Rev. Drug Disc., 2009, 8, 41-54; Conn et al, Nat. Rev. Drug.Disc., 2014, 13, 692-708). Furthermore, the effect of an allostericmodulator is self-limiting when it stabilizes the binding of the agonistin high concentrations. This in turn results, in principle, in a morefavourable pharmacological safety profile compared to agonists, sincetoxic effects caused by receptor overactivation are limited(Christopoulos, Mol. Pharmacol., 2014, 86, 463-478).

The mutual influencing of allosteric and orthosteric ligands in terms ofaffinity and intrinsic activity, which is referred to as cooperativity,is determined by both ligands. In the case of a positive allostericmodulator of M2R, the effects of ACh (orthosteric ligand) are enhanced(positive cooperativity). Because of their ability to modulate receptorconformations in the presence of an orthosteric ligand, allostericligands can bring about fine adjustment of pharmacological effects (Wanget al., J. Pharmacol. Exp. Therap., 2009, 331, 340-348). In the case ofthe positive allosteric modulator of M2R, this suggests an advantageouseffect profile, a reduced risk of side effects and a starting point forthe development of more subtype-selective ligands compared to a fullagonist.

The crystal structure of the positive allosteric M4R and M2R ligandLY2119620(3-amino-5-chloro-N-cyclopropyl-4-methyl-6-[2-(4-methylpiperazin-1-yl)-2-oxoethoxy]thieno[2,3-b]pyridine-2-carboxamide)in a complex with M2R has been published. The allosteric binding site ofM2R is spatially adjacent to but clearly delimited from the orthostericbinding site and, compared to the other muscarinic receptor subtypes,exhibits lower conservation, i.e. has greater differences in sequence(Kruse et al., Nature, 2013, 504, 101-106). LY2119620 was described asan unselective M2R/M4R positive allosteric modulator (Croy et al.,Molecular Pharmacology, July 2014 86, 1, 106-115; Schober et al.,Molecular Pharmacology, July 2014 86, 1, 116-123).

M2R as a constituent of the autonomic nervous system plays an importantrole in the pathogenesis and progression of cardiovascular disorders.Autonomic imbalance characterized by vagal (parasympathetic) weakeningand dominance of the sympathetic nervous system is closely correlated toincreased morbidity and mortality. The clinical and prognosticsignificance of autonomic imbalance is well-documented in variouscardiovascular disorders, including heart failure (HF), heart rhythmdisorders, ischaemia/reperfusion (I/R), hypertension (He et al., Br. J.Pharmacol. 2014, Epub) and chronic kidney disease (Ranpuria et al.,Nephrol Dial Transplant. 2008, 23(2), 444-4499). Particularly in thecase of patients having comorbidities such as diabetes, autonomicimbalance can contribute to increased morbidity and mortality (Vinik etal., Diabet Med., 2011, 28(6), 643-651). Baroreceptor reflexdysfunctions, such as hypertensive crises or variability in high bloodpressure, as signs of a dysfunctional autonomic nervous system, oftenaccompany the acute phase of ischaemic or haemorrhagic stroke (Sykora etal., Stroke, 2009, 40(12), 678-682).

The frequent observation of comorbidity between cardiovascular andpsychological disorders, such as between heart failure and depression,is probably based on common pathomechanisms that accompany the autonomicimbalance (Halaris et al., Mod Trends Pharmacopsychiatri., 2013, 28,144-161). Chronic stress shifts the homeostatic equilibrium of theautonomic nervous system. Reduced vagal tone contributes topro-inflammatory status, with impairment of neurotransmitter regulation,especially serotonergic transmission. Other psychological disorders havealso been connected to autonomic dysregulation, for example attentiondeficit/hyperactivity disorder (ADHD), which is characterized by loss ofinhibition, lack of emotional self-control, inattentiveness andhyperactivity (Rash and Aguirre-Camacho, Atten Defic Hyperact Disord.,2012, 4(4), 167-177).

Boosting parasympathetic activity by means of a positive allostericmodulator, including expected anti-inflammatory effects, elevation ofnitrogen monoxide (NO), regulation of redox state, improvement ofmitochondrial function and of calcium regulation, could thereforeconstitute a novel therapeutic principle, especially in the case ofcardiovascular disorders. There are numerous pointers that themodulation of parasympathetic activity can be considered as a potentialtherapy target in the event of chronic heart failure. Vagal nervestimulation in dogs that have recovered from myocardial infarctionsignificantly lowered the incidence of sudden cardiac death, andmortality in rats suffering from chronic heart failure (De Ferrari, J.Cardiovasc. Transl. Res., 2014, 7(3), 310-320). In a dog model withheart failure (LVEF 35%) and an implanted vagal stimulator, it was shownthat, in the treatment group compared to the sham group, a significantimprovement in the left-ventricular ejection fraction (LVEF) andreduction in the end-systolic and -diastolic volumes (LVESV, LVEDV)occurred, as did a significant reduction in heart rate within 3 months.The described effect of the VNS was additive to beta-blockeradministration (De Ferrari, J. Cardiovasc. Transl. Res., 2014, 7(3),310-320). The plasma level for TNF-α and IL-6 and the myocardial proteinexpression thereof was lowered by vagal stimulation in this animalmodel, which suggests that boosting of the parasympathetic nervoussystem, as well as the effects on LV remodelling, also has positiveeffects on pro-inflammatory cytokines.

Based on experimental preclinical data, the first clinical studies onvagal stimulation in patients having chronic heart failure have now beendone, as already established in the treatment of epilepsy anddepression. The effect of boosting the parasympathetic system via directvagal nerve stimulation (VNS) was assessed in a non-randomizedobservation study with 32 patients having left-ventricular (LV) systolicdysfunction, and the results suggest that vagal stimulation has afavourable effect on quality of life, stamina and LV remodelling (DeFerrari G M et al., Eur. Heart J., 2011, 32, 847-855). In themulti-centre open-label feasibility study ANTHEM-HF, the safety,compatibility and efficacy of vagal stimulation in patients havingchronic stable symptomatic heart failure with reduced ejection fraction(HFrEF) were examined in addition to the standard treatment (Premchand RK et al., J. Card. Fail., 2014, 20(11), 808-816). The continuous vagalnerve stimulation employed in this study led to an improvement in theejection fraction, variability of heart rate, NYHA class and quality oflife. The first placebo-controlled clinical study NECTAR-HF, incontrast, did not show any significant effect of vagal nerve stimulationon the heart function of HF patients after 6 months (Zannad et al., Eur.Heart J., 2015, 36(7), 425-433). The only improvement was in quality oflife. The INOVATE-HF study with 650 HF patients was unable to show anyeffects of this treatment in relation to mortality and hospitalization.(Gold et al., J Am Coll Cardiol., 2016, Mar. 29. pii:S0735-1097(16)32404-4. doi: 10.1016/j.jacc.2016.03.525). Quality of lifeand walking distance were significantly improved.

As well as the infection risk and the potential risks of a surgicalintervention, treatment by means of electrical stimulation of the vagalnerve is limited by side effects such as dysphonia, coughing andoropharyngeal pain (Premchand R K et al., J. Card. Fail., 2014, 20(11),808-816). Medication-assisted boosting of the parasympathetic nervoussystem by a direct effect on M2R could constitute a novel therapyoption.

Atrial fibrillation is the most common persistent heart rhythm disorder,and the prevalence thereof increases with age (Chen et al., Circ. Res.,2014, 114(9), 1500-1515). Atrial fibrillation and heart failure oftenoccur together in a mutually beneficial relationship. Thus, theprevalence of atrial fibrillation increases with the clinical severityof heart failure (Maisel and Stevenson, Am. J. Cardiol., 2003, 91,(suppl) 2D-8D). Clinical data suggest that patients where heart failureis accompanied by atrial fibrillation have a poor prognosis. Bothlethality (total lethality, sudden death and pump failure) and morbidity(hospitalization) were found to be significantly increased in this groupof patients.

In the treatment of atrial fibrillation, there are two distincttreatment strategies: what is called rate control with adjustment and ifat all possible normalization of ventricular frequency, and what iscalled rhythm control, comprising measures intended to establish ormaintain a sinusoidal rhythm. An effective treatment consists of acombination of non-medication-assisted and medication-assisted orintervention measures (Levalter T, Fortbildungsprogramm Pharmazie, 2011,5, 106-127).

For medication-assisted rhythm control after cardioversion,beta-blockers, class I and class III antiarrhythmics are used accordingto the underlying cardiac disorder and the extent of left-ventricularpumping function impairment. In patients having permanent atrialfibrillation and in oligosymptomatic (frequently older) patients havingpersistent or paroxysmal atrial fibrillation, simple rate control withretention and allowance of the atrial fibrillation is often the therapyof choice. Primarily medicaments that affect the refractory period orthe conduction capacity of the AV node are used. In principle, thiseffect can be achieved by stimulation of the M2R, which plays the keyphysiological role at this point, for example with the aid of a positiveallosteric modulator. The drugs available to date are beta-blockers,digitalis, calcium antagonists and, in individual cases, amiodarone,which are used with consideration of the lifestyle, underlying cardiacdisorder and any secondary disorders. Especially in patients havingreduced left ventricular pumping function and severe heart failure,however, the options for medication-assisted therapy are inadequate.Calcium antagonists are contraindicated in this group of patients. Asthe most recent studies have shown, treatment with digoxin leads toincreased mortality of patients having atrial fibrillation (Leong-Sitand Tang, Curr. Opin. Cardiol., 2015, Epub). For beta-blockers, a lackof effectiveness in patients having atrial fibrillation and heartfailure was shown in a meta analysis (Leong-Sit and Tang, Curr. Opin.Cardiol., 2015, Epub). The medical demand for novel efficient and safetreatments for rate control is correspondingly high. This could beachieved by medication-assisted stimulation of M2R.

The problem addressed by the present invention is that of identifyingand providing novel substances which constitute potent, positiveallosteric modulators of the muscarinic M2 receptor and as such aresuitable for treatment and/or prevention particularly of cardiovasculardisorders and/or renal disorders.

1-Benzyl-substituted 4-oxo-1,4-dihydroquinoline-3-carboxylic acids havebeen described as allosteric modulators of the M1 muscarine receptor fortreatment of neurodegenerative disorders such as Alzheimer's andschizophrenia (Scammells et al., ACS Chem. Neurosci., 2013, 4 (7),1026-1048; Mistry et al., J. Med. Chem. 2013, 56, 5151-5172). Amongother documents, EP 0945435 B1 discloses pyridonecarboxylic acidderivatives having antibacterial activity. WO 2002/085886-A2, WO2003/050107-A1 and WO 2005/026145-A2 claim 7-piperidino-substitutedquinolonecarboxylic acid derivatives, and WO 2005/026165-A1 and WO2005/049602-A1 various 7-pyrrolidino-substituted quinolonecarboxylicacid derivatives, and EP 1650192-A1 specific7-azetidinylquinolonecarboxylic acid derivatives havingantimicrobial/antibacterial activity. WO 2005/009971-A1 and JP2005012561 disclose quinolone derivatives which can be used as plateletaggregation inhibitors.

The present invention relates to positive allosteric modulators of themuscarinic M2 receptor for use in the treatment and/or prevention ofdisorders, especially of cardiovascular disorders and/or renaldisorders.

The inventors have found that, surprisingly, the positive allostericmodulation of the muscarinic M2 receptor is particularly suitable forthe treatment of cardiovascular disorders, preferably according to theaforementioned list of indications.

The positive allosteric M4R and M2R ligand LY2119620 is associatedpredominantly with neural and psychological disorders (Croy et al.,Molecular Pharmacology, July 2014, 86, 1, 106-115). Molecules having aprofile corresponding or similar to that of LY2119620 are thusunsuitable for a selected allosteric modification of the muscarinic M2receptor, and hence treatment of cardiovascular disorders according tothe aforementioned list of indications with a low level of side effects.

In an advantageous embodiment of the present invention, the inventivepositive allosteric modulators of the muscarinic M2 receptor havesubtype selectivity for the M2 receptor with regard to the positiveallosteric effect.

In a particular embodiment, these have, within a concentration range of1 μM-10 μM, an identical or higher selectivity for the muscarinic M2receptor than for the muscarinic M4 receptor. It is further preferablethat the selectivity of the allosteric modulator for the muscarinic M2receptor is at least 1.1 times, 1.2 times, 1.3 times or, morepreferably, 1.4 times higher than that for the muscarinic M4 receptor.

In a further particular embodiment, these have, within a concentrationrange of 5 μM-20 μM, a selectivity at least 4 times higher for themuscarinic M2 receptor than for the muscarinic M1 receptor. It ispreferably the case that the selectivity of the allosteric modulator forthe muscarinic M2 receptor is at least 4.2 times, 4.3 times, 4.4 times,4.5 times, 4.6 times, 4.7 times, 4.8 times, 4.9 times, 5 times, 5.1times, 5.2 times, 5.3 times, 5.4 times, 5.5 times, 5.6 times, 5.7 timesor, more preferably, 5.8 times higher than for the muscarinic M1receptor.

The selectivity is determined here as the quotient of the respectivemodulator-related allosteric shift in the EC₅₀ value of the AChdose-response curve for the M2 receptor relative to the respective otherMx receptor type. To determine said quotient, first of all, the EC₅₀value of the ACh dose-response curve is determined for the particularreceptors (“EC₅₀ ACh”). Subsequently, the allosteric shift in the EC₅₀value of ACh (“shift EC₅₀”) is determined after administration of 1 μMor 10 μM of the allosteric modulator to be tested. Especially suitablefor this purpose is the protocol of the Eurofin functional Ca²⁺ releasetest described on pages 610-612, section B-3. (GPCRProfiler® “Servicesin agonistic and allosteric mode for Mx Receptors”). Finally, quotientsof the allosteric shift for the M2 receptor relative to the respectiveMx receptor (e.g. M1R, M4R) are formed, which function in turn as ameasure of the respective selectivity.

The invention especially relates to compounds of the general formula (I)

in which

-   R¹ is NR⁴R⁵,    -   in which    -   R⁴ is hydrogen, methyl, (C₂-C₄)-alkyl or (C₃-C₆)-cycloalkyl,        -   where (C₂-C₄)-alkyl may be substituted by hydroxyl or up to            trisubstituted by fluorine    -   and    -   R⁵ is (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl, 3- to 6-membered        saturated heterocyclyl or (C₁-C₄)-alkylsulphonyl,        -   where (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl and 3- to 6-membered            saturated heterocyclyl may be up to trisubstituted,            identically or differently, by methyl, difluoromethyl,            trifluoromethyl, hydroxyl, hydroxycarbonyl, oxo, methoxy,            difluoromethoxy, trifluoromethoxy and cyano, and            additionally up to tetrasubstituted by fluorine,    -   or    -   R⁴ and R⁵ together with the nitrogen atom to which they are        bonded form a saturated or partially unsaturated, 3- to        6-membered monocyclic or 6- to 10-membered bicyclic heterocycle        which may contain one or two further, identical or different        heteroatoms from the group of N, O, S, SO and/or SO₂ as ring        members,        -   where the 3- to 6-membered monocyclic and the 6- to            10-membered bicyclic heterocycle may each be substituted by            1 to 5 substituents independently selected from the group of            (C₁-C₄)alkyl, difluoromethyl, trifluoromethyl, hydroxy,            hydroxycarbonyl, oxo, (C₁-C₃)-alkoxy, difluoromethoxy,            trifluoromethoxy, cyano, (C₁-C₃)-alkoxycarbonyl,            aminocarbonyl, mono-(C₁-C₃)alkylaminocarbonyloxy,            —NHC(═O)R^(22A) and —CH₂NHC(═O)R^(22B), and additionally up            to tetrasubstituted by fluorine, in which            -   R^(22A) and R^(22B) independently represent                (C₁-C₃)-alkyl or cyclopropyl,            -   and            -   in which (C₁-C₄)-alkyl may be mono- or disubstituted,                identically or differently, by hydroxyl and                (C₁-C₃)-alkoxy, and up to tetrasubstituted by fluorine,-   R² is a group of the formula

-   -   in which    -   * marks the bonding site to the nitrogen atom of the amide        moiety,    -   R^(6A) is hydrogen or (C₁-C₄)-alkyl,    -   R^(6B) is hydrogen, (C₁-C₄)-alkyl, cyclopropyl, trifluoromethyl,        methoxymethyl or trifluoromethoxymethyl,    -   R⁷ is (C₁-C₄)-alkyl, cyclopropyl or cyclobutyl,        -   where (C₁-C₄)-alkyl may be up to pentasubstituted and            cyclopropyl and cyclobutyl up to tetrasubstituted by            fluorine,    -   Y¹ is —(CH₂)_(k)—, —CF₂—, —O—CH₂—, —CH₂—O— or —CH₂—O—CH₂—,        -   in which        -   k is 0, 1, 2 or 3,    -   R⁸ is up to penta-fluorine-substituted (C₁-C₂)-alkyl or        trifluoromethoxymethyl,    -   L¹ is a bond or a group of the formula        —C(R^(9A)R^(9B))—(C(R^(10A)R^(10B)))_(m)—,        -   in which        -   m represents 0 or 1,        -   R^(9A) represents hydrogen or methyl,        -   R^(9B) represents hydrogen, methyl, trifluoromethyl,            pentafluoroethyl or trifluoromethoxymethyl,        -   R^(10A) and R^(10B) independently represent hydrogen or            methyl,    -   Ar² is phenyl,        -   where phenyl may be mono- to trisubstituted, identically or            differently, by fluorine, chlorine, (C₁-C₃)-alkyl,            difluoromethoxymethyl, trifluoromethoxymethyl and/or            trifluoromethyl,    -   or    -   is a 5- to 10-membered bicyclic or tricyclic carbocycle,    -   where the 5- to 10-membered bicyclic or tricyclic carbocycle may        be up to trisubstituted, identically or differently, by        (C₁-C₃)-alkyl and trifluoromethyl, and additionally up to        tetrasubstituted by fluorine,

-   Ar¹ is a group of the formula

-   -   in which    -   ** marks the bonding site to the nitrogen atom,    -   R^(3A) is fluorine, chlorine or trifluoromethyl,    -   R^(3B) is hydrogen or fluorine    -   and    -   R^(3C) is hydrogen, fluorine or chlorine        and the N-oxides, salts, solvates, salts of the N-oxides and        solvates of the N-oxides or salts thereof.

Compounds according to the invention are the compounds of the formula(I) and the salts, solvates and solvates of the salts thereof, thecompounds that are encompassed by formula (I) and are of the formulaementioned below and the salts, solvates and solvates of the saltsthereof and the compounds that are encompassed by the formula (I) andare mentioned below as embodiments and the salts, solvates and solvatesof the salts thereof if the compounds that are encompassed by theformula (I) and are mentioned below are not already salts, solvates andsolvates of the salts.

Compounds according to the invention are likewise N-oxides of thecompounds of the formula (I) and the salts, solvates and solvates of thesalts thereof.

Preferred salts in the context of the present invention arephysiologically acceptable salts of the compounds according to theinvention. Also encompassed are salts which are not themselves suitablefor pharmaceutical applications but can be used, for example, for theisolation, purification or storage of the compounds according to theinvention.

Physiologically acceptable salts of the compounds according to theinvention include acid addition salts of mineral acids, carboxylic acidsand sulphonic acids, for example salts of hydrochloric acid, hydrobromicacid, sulphuric acid, phosphoric acid, methanesulphonic acid,ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid,naphthalenedisulphonic acid, acetic acid, trifluoroacetic acid,propionic acid, lactic acid, tartaric acid, malic acid, citric acid,fumaric acid, maleic acid and benzoic acid.

Physiologically unacceptable salts of the compounds according to theinvention also include salts of conventional bases, by way of exampleand with preference alkali metal salts (e.g. sodium and potassiumsalts), alkaline earth metal salts (e.g. calcium and magnesium salts),zinc salts and ammonium salts derived from ammonia or organic amineshaving 1 to 16 carbon atoms, by way of example and with preferenceethylamine, diethylamine, triethylamine, DIPEA, monoethanolamine,diethanolamine, triethanolamine, dimethylaminoethanol,diethylaminoethanol, tris(hydroxymethyl)aminomethane, choline, procaine,dicyclohexylamine, dibenzylamine, N-methylmorpholine,N-methylpiperidine, arginine, lysine and 1,2-ethylenediamine.

Solvates in the context of the invention are described as those forms ofthe compounds according to the invention which form a complex in thesolid or liquid state by coordination with solvent molecules. Hydratesare a specific form of the solvates in which the coordination is withwater. Solvates preferred in the context of the present invention arehydrates.

The compounds according to the invention may, depending on theirstructure, exist in different stereoisomeric forms, i.e. in the form ofconfigurational isomers or else, if appropriate, as conformationalisomers (enantiomers and/or diastereomers, including those in the caseof atropisomers). The present invention therefore encompasses theenantiomers and diastereomers, and the respective mixtures thereof. Itis possible to isolate the stereoisomerically homogeneous constituentsfrom such mixtures of enantiomers and/or diastereomers in a knownmanner. Preference is given to employing chromatographic methods forthis purpose, especially HPLC chromatography on achiral or chiralseparation phases. In the case of carboxylic acids as intermediates orend products, separation is alternatively also possible viadiastereomeric salts using chiral amine bases.

In the context of the present invention, the term “enantiomericallypure” is understood to the effect that the compound in question withrespect to the absolute configuration of the chiral centres is presentin an enantiomeric excess of more than 95%, preferably more than 98%.The enantiomeric excess, ee, is calculated here by evaluating an HPLCanalysis chromatogram on a chiral phase using the formula below:

${ee} = {{\frac{{{Enantiomer}\mspace{14mu} 1\mspace{14mu} \left( {{area}\mspace{14mu} {percent}} \right)} - {{Enantiomer}\mspace{14mu} 2\mspace{14mu} \left( {{area}\mspace{14mu} {percent}} \right)}}{{{Enantiomer}\mspace{14mu} 1\mspace{14mu} \left( {{area}\mspace{14mu} {percent}} \right)} + {{Enantiomer}\mspace{14mu} 2\mspace{20mu} \left( {{area}\mspace{14mu} {percent}} \right)}}} \times 100{\%.}}$

If the compounds according to the invention can occur in tautomericforms, the present invention encompasses all the tautomeric forms.

The present invention also encompasses all suitable isotopic variants ofthe compounds according to the invention. An isotopic variant of acompound according to the invention is understood here to mean acompound in which at least one atom within the compound according to theinvention has been exchanged for another atom of the same atomic number,but with a different atomic mass from the atomic mass which usually orpredominantly occurs in nature (“unnatural fraction”). The expression“unnatural fraction” is understood to mean a fraction of such an isotopehigher than its natural frequency. The natural frequencies of isotopesto be employed in this connection can be found in “Isotopic Compositionsof the Elements 1997”, Pure Appl. Chem., 70(1), 217-235, 1998. Examplesof isotopes which can be incorporated into a compound according to theinvention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus,sulphur, fluorine, chlorine, bromine and iodine, such as ²H (deuterium),³H (tritium), ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³²P, ³³P, ³³S, ³⁴S, ³⁵S, ³⁶S, 18F³⁶Cl, ⁸²Br, ¹²³I, ¹²⁴I, ¹²⁹I and ¹³¹I. Particular isotopic variants of acompound according to the invention, especially those in which one ormore radioactive isotopes have been incorporated, may be beneficial, forexample, for the examination of the mechanism of action or of the drugdistribution in the body; due to comparatively easy preparability anddetectability, especially compounds labelled with ³H or ¹⁴C isotopes aresuitable for this purpose. In addition, the incorporation of isotopes,for example of deuterium, can lead to particular therapeutic benefits asa consequence of greater metabolic stability of the compound, forexample an extension of the half-life in the body or a reduction in theactive dose required; such modifications of the compounds according tothe invention may therefore possibly also constitute a preferredembodiment of the present invention. With regard to the treatment and/orprophylaxis of the disorders specified here, the isotopic variant(s) ofthe compounds of the general formula (I) preferably contain deuterium(“deuterium-containing compounds of the general formula (I)”). Isotopicvariants of the compounds of the general formula (I) into which one ormore radioactive isotopes such as ³H or ¹⁴C have been incorporated arebeneficial, for example, in medicament and/or substrate tissuedistribution studies. Because of their easy incorporability anddetectability, these isotopes are particularly preferred. It is possibleto incorporate positron-emitting isotopes such as ¹⁸F or 11C into acompound of the general formula (I). These isotopic variants of thecompounds of the general formula (I) are suitable for use in in vivoimaging applications. Deuterium-containing and ¹³C-containing compoundsof the general formula (I) can be used within the scope of preclinicalor clinical studies in mass spectrometry analyses (H. J. Leis et al.,Curr. Org. Chem., 1998, 2, 131). Isotopic variants of the compoundsaccording to the invention can be prepared by commonly used processesknown to those skilled in the art, for example by the methods describedfurther down and the procedures described in the working examples, byusing corresponding isotopic modifications of the respective reagentsand/or starting compounds.

Isotopic variants of the compounds of the general formula (I) can beprepared by processes known to those skilled in the art as described inthe schemes and/or examples described here, by replacing a reagent withan isotopic variant of the reagent, preferably a deuterium-containingreagent. According to the deuteration sites desired, it is possible insome cases to incorporate deuterium from D₂O directly into the compoundsor into reagents which can be used for the synthesis of such compounds(Esaki et al., Tetrahedron, 2006, 62, 10954; Esaki et al., Chem. Eur.J., 2007, 13, 4052). Another useful reagent for incorporation ofdeuterium into molecules is deuterium gas. A rapid route forincorporation of deuterium is the catalytic deuteration of olefinicbonds (H. J. Leis et al., Curr. Org. Chem., 1998, 2, 131; J. R. Morandiet al., J. Org. Chem., 1969, 34 (6), 1889) and acetylenic bonds (N. H.Khan, J. Am. Chem. Soc., 1952, 74 (12), 3018; S. Chandrasekhar et al.,Tetrahedron, 2011, 52, 3865). For direct exchange of hydrogen fordeuterium in hydrocarbons containing functional groups, it is alsopossible to use metal catalysts (i.e. Pd, Pt and Rh) in the presence ofdeuterium gas (J. G. Atkinson et al., U.S. Pat. No. 3,966,781). Variousdeuterated reagents and synthesis units are commercially available fromcompanies like, for example, C/D/N Isotopes, Quebec, Canada; CambridgeIsotope Laboratories Inc., Andover, Mass., USA; and CombiPhos Catalysts,Inc., Princeton, N.J., USA. Further information relating to the priorart with regard to deuterium-hydrogen exchange can be found, forexample, in Hanzlik et al., J. Org. Chem., 1990, 55, 3992-3997; R. P.Hanzlik et al., Biochem. Biophys. Res. Commun., 1989, 160, 844; P. J.Reider et al., J. Org. Chem., 1987, 52, 3326-3334; M. Jarman et al.,Carcinogenesis, 1993, 16(4), 683-688; J. Atzrodt et al., Angew. Chem.,Int. Ed. 2007, 46, 7744; K. Matoishi et al., 2000, J. Chem. Soc, Chem.Commun., 1519-1520; K. Kassahun et al., WO 2012/112363.

The term “deuterium-containing compound of the general formula (I)” isdefined as a compound of the general formula (I) in which one or morehydrogen atoms have been replaced by one or more deuterium atoms and inwhich the frequency of deuterium in every deuterated position in thecompound of the general formula (I) is higher than the natural frequencyof deuterium, which is about 0.015%. More particularly, in adeuterium-containing compound of the general formula (I), the frequencyof deuterium in every deuterated position in the compound of the generalformula (I) is higher than 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80%,preferably higher than 90%, 95%, 96% or 97%, even further preferablyhigher than 98% or 99%, in this position or these positions. It will beapparent that the frequency of deuterium in every deuterated position isindependent of the frequency of deuterium in other deuterated positions.

The selective incorporation of one or more deuterium atoms into acompound of the general formula (I) can alter the physicochemicalproperties (for example acidity [A. Streitwieser et al., J. Am. Chem.Soc., 1963, 85, 2759; C. L. Perrin et al., J. Am. Chem. Soc., 2007, 129,4490], basicity [C. L. Perrin, et al., J. Am. Chem. Soc., 2003, 125,15008; C. L. Perrin in Advances in Physical Organic Chemistry, 44, 144;C. L. Perrin et al., J. Am. Chem. Soc., 2005, 127, 9641], lipophilicity[B. Testa et al., Int. J. Pharm., 1984, 19(3), 271]) and/or themetabolic profile of the molecule, and cause changes in the ratio ofparent compound to metabolites or the amounts of metabolites formed.Such changes may lead to particular therapeutic benefits and thereforebe preferable under particular circumstances. Reduced rates ofmetabolism and metabolic switching, where the ratio of metabolites ischanged, have been reported (D. J. Kushner et al., Can. J. Physiol.Pharmacol., 1999, 77, 79; A. E. Mutlib et al., Toxicol. Appl.Pharmacol., 2000, 169, 102). These changes in the exposure to parentdrug and metabolites can have important consequences with respect to thepharmacodynamics, tolerability and efficacy of a deuterium-containingcompound of the general formula (I). In some cases deuteriumsubstitution reduces or eliminates the formation of an undesired ortoxic metabolite and enhances the formation of a desired metabolite(e.g. Nevirapine: A. M. Sharma et al., Chem. Res. Toxicol., 2013, 26,410; Uetrecht et al., Chemical Research in Toxicology, 2008, 21, 9,1862; Efavirenz: A. E. Mutlib et al., Toxicol. Appl. Pharmacol., 2000,169, 102). In other cases the major effect of deuteration is to reducethe rate of systemic clearance. As a result, the biological half-life ofthe compound is increased. The potential clinical benefits would includethe ability to maintain similar systemic exposure with decreased peaklevels and increased trough levels. This could result in lower sideeffects and enhanced efficacy, depending on the particular compound'spharmacokinetic/pharmacodynamic relationship. Indiplon (A. J. Morales etal., Abstract 285, The 15th North American Meeting of the InternationalSociety of Xenobiotics, San Diego, Calif., Oct. 12-16, 2008), ML-337 (C.J. Wenthur et al., J. Med. Chem., 2013, 56, 5208), and Odanacatib (K.Kassahun et al., WO2012/112363) are examples for this deuterium effect.Still other cases have been reported in which reduced rates ofmetabolism result in an increase in exposure of the drug withoutchanging the rate of systemic clearance (e.g. Rofecoxib: F. Schneider etal., Arzneim. Forsch. Drug. Res., 2006, 56, 295; Telaprevir: F. Maltaiset al., J. Med. Chem., 2009, 52, 7993). Deuterated drugs showing thiseffect may have reduced dosing requirements (e.g. lower number of dosesor lower dosage to achieve the desired effect) and/or may produce lowermetabolite loads.

A compound of general formula (I) may have multiple potential sites ofattack for metabolism. To optimize the above-described effects onphysicochemical properties and metabolic profile, deuterium-containingcompounds of general formula (I) having a certain pattern of one or moredeuterium-hydrogen exchange(s) can be selected. Particularly, thedeuterium atom(s) of deuterium-containing compound(s) of general formula(I) is/are attached to a carbon atom and/or is/are located at thosepositions of the compound of general formula (I), which are sites ofattack for metabolizing enzymes such as e.g. cytochrome P₄₅₀.

In the context of the present invention, unless specified otherwise, thesubstituents are defined as follows:

Alkyl per se and “Alk” and “alkyl” in alkoxy, alkylsulphonyl,alkylaminocarbonyloxy and alkoxycarbonyl are a linear or branched alkylradical having generally 1 to 6 and preferably 1 to 4 carbon atoms, byway of example and with preference methyl, ethyl, n-propyl, isopropyl,tert-butyl, isobutyl (2-methylprop-1-yl), n-pentyl and n-hexyl.

Alkoxy is, by way of example and with preference, methoxy, ethoxy,n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

Alkylaminocarbonyloxy is an alkylaminocarbonyloxy radical having one ortwo (independently chosen) alkyl substituents.(C₁-C₃)-Alkylaminocarbonyloxy is, for example, amonoalkylaminocarbonyloxy radical having 1 to 3 carbon atoms or adialkylaminocarbonyloxy radical having 1 to 3 carbon atoms in each alkylsubstituent. Preferred examples include: methylaminocarbonyloxy,ethylaminocarbonyloxy, n-propylaminocarbonyloxy,isopropylaminocarbonyloxy, tert-butylaminocarbonyloxy,n-pentylaminocarbonyloxy, n-hexylaminocarbonyloxy,N,N-dimethylaminocarbonyloxy, N,N-diethylaminocarbonyloxy,N-ethyl-N-methylaminocarbonyloxy, N-methyl-N-n-propylaminocarbonyloxy,N-isopropyl-N-n-propylaminocarbonyloxy,N-tert-butyl-N-methylaminocarbonyl, N-ethyl-N-n-pentylamino-carbonyl andN-n-hexyl-N-methylaminocarbonyloxy.

Alkylsulphonyl in the context of the invention is a straight-chain orbranched alkyl radical which has 1 to 4 carbon atoms and is bonded via asulphonyl group. Preferred examples include: methylsulphonyl,ethylsulphonyl, n-propylsulphonyl, isopropylsulphonyl, n-butylsulphonyland tert-butylsulphonyl.

Alkoxvcarbonyl is, by way of example and with preference,methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl,tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.

Carbocycle in the context of the invention is a mono-, bi-, tri- orspirocyclic, saturated or partially unsaturated carbon cycle having atotal of 3 to 10 ring atoms and up to 2 double bonds. A monocyclicsaturated carbocycle is referred to synonymously as cycloalkyl. Examplesinclude: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl,cycloheptadienyl, spiro[2.3]hexyl, spiro[2.4]heptyl, spiro[2.5]octyl,bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl,tricyclo[3.3.1.1^(3,7)]decyl. Preference is given to monocycliccycloalkyl having 3 to 6 carbon atoms and bicyclic or tricyclicsaturated carbocyclyl having 7 to 10 carbon atoms. Preferred examplesinclude: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,bicyclo[1.1.1]pentyl, spiro[2.5]octyl, bicyclo[2.2.1]heptyl,bicyclo[2.2.2]octyl, tricyclo[3.3.1.1^(3,7)]decyl.

Cycloalkyl in the context of the invention is a monocyclic saturatedcycloalkyl group having generally 3 to 8 and preferably 3 to 6 carbonatoms; preferred examples are cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl.

Heterocyclyl is a mono-, poly- or spirocyclic, preferably mono-, bi- orspirocyclic, nonaromatic heterocyclic radical having generally 3 to 10ring atoms and up to 3, preferably up to 2, heteroatoms and/or heterogroups from the group of N, O, S, SO, SO₂. The heterocyclyl radicals maybe saturated or partially unsaturated. Preference is given to 4- to6-membered monocyclic saturated heterocyclyl radicals having onenitrogen atom and to those having one further heteroatom from the groupof N, O, S, SO and SO₂, and 6- to 10-membered bicyclic saturatedheterocyclyl radicals having one nitrogen atom and those having onefurther heteroatom from the group of N, O, S, SO and SO₂. Preferredexamples include: aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, oxazolidinyl, thiazolidinyl, thiadiazolidinyl,imidazolidinyl, imidazolidin-2-ylidene, morpholinyl,azaspiro[2.4]heptyl, azaspiro[3.3]heptyl, azabicyclo[3.1.0]hexyl,azabicyclo[3.2.1]octyl, perhydropyrrolo[3,4-c]pyrrolyl.

Halogen is fluorine, chlorine, bromine and iodine.

In the group of the formula that R², Ar¹ or Q may represent, the endpoint of the line marked by #¹, #², #²; *, ** and *** is not a carbonatom or a CH₂ group, but is part of the bond to the respective atom towhich R², Ar¹; Ar² or Q is bonded.

When radicals in the compounds according to the invention aresubstituted, the radicals may be mono- or polysubstituted, unlessspecified otherwise. In the context of the present invention, allradicals which occur more than once are defined independently of oneanother. When radicals in the compounds according to the invention aresubstituted, the radicals may be mono- or polysubstituted, unlessspecified otherwise. Substitution by one substituent or by two identicalor different substituents is preferred.

In the context of the present invention, the term “treatment” or“treating” includes inhibition, retardation, checking, alleviating,attenuating, restricting, reducing, suppressing, repelling or healing ofa disease, a condition, a disorder, an injury or a health problem, orthe development, the course or the progression of such states and/or thesymptoms of such states. The term “therapy” is understood here to besynonymous with the term “treatment”.

The terms “prevention”, “prophylaxis” and “preclusion” are usedsynonymously in the context of the present invention and refer to theavoidance or reduction of the risk of contracting, experiencing,suffering from or having a disease, a condition, a disorder, an injuryor a health problem, or a development or advancement of such statesand/or the symptoms of such states.

The treatment or prevention of a disease, a condition, a disorder, aninjury or a health problem may be partial or complete.

Preference is given in the context of the present invention to compoundsof the formula (I) in which

-   R¹ is NR⁴R⁵ in which    -   R⁴ is hydrogen, methyl, up to tri-fluorine-substituted        (C₂-C₄)-alkyl or (C₃-C₆)-cycloalkyl,    -   and    -   R⁵ is (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl, 3- to 6-membered        saturated heterocyclyl or (C₁-C₄)-alkylsulphonyl,        -   where (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl and 3- to 6-membered            saturated heterocyclyl may be up to trisubstituted,            identically or differently, by methyl, difluoromethyl,            trifluoromethyl, hydroxyl, oxo, methoxy, difluoromethoxy and            trifluoromethoxy, and additionally up to tetrasubstituted by            fluorine,    -   or    -   R⁴ and R⁵ together with the nitrogen atom to which they are        bonded form a saturated or partially unsaturated, 3- to        6-membered monocyclic or 6- to 10-membered bicyclic heterocycle        which may contain one or two further, identical or different        heteroatoms from the group of N, O, S, SO and/or SO₂ as ring        members,        -   where the 3- to 6-membered monocyclic and the 6- to            10-membered bicyclic heterocycle may each be substituted by            1 to 5 substituents independently selected from the group of            (C₁-C₄)alkyl, difluoromethyl, trifluoromethyl, hydroxy, oxo,            (C₁-C₃)-alkoxy, difluoromethoxy, trifluoromethoxy, cyano,            (C₁-C₃)-alkoxycarbonyl, aminocarbonyl and            mono-(C₁-C₃)-alkylaminocarbonyloxy, and additionally up to            tetrasubstituted by fluorine,        -   in which (C₁-C₄)-alkyl may be mono- or disubstituted,            identically or differently, by hydroxyl and (C₁-C₃)-alkoxy,            and up to tetrasubstituted by fluorine,-   R² is tert-butyl, 2-methylbutyl    -   or    -   is a group of the formula

-   -   in which    -   * marks the bonding site to the nitrogen atom of the amide        moiety,    -   R^(6A) is hydrogen or (C₁-C₄)-alkyl,    -   R^(6B) is hydrogen, trifluoromethyl or trifluoromethoxymethyl,    -   R⁷ is (C₁-C₄)-alkyl or cyclopropyl,        -   where (C₁-C₄)-alkyl may be up to pentasubstituted and            cyclopropyl up to tetrasubstituted by fluorine,    -   Y¹ is —(CH₂)_(k)—, —O—CH₂—, —CH₂—O— or —CH₂—O—CH₂—,        -   in which        -   k is 1, 2 or 3,    -   R⁸ is up to penta-fluorine-substituted (C₁-C₂)-alkyl,    -   L¹ is a bond or a group of the formula        —CR^(9A)R^(9B)—(CR^(10A)R^(10B))_(m)—,        -   in which        -   m represents 0 or 1,        -   R^(9A) represents hydrogen or methyl,        -   R^(9B) represents hydrogen, methyl, trifluoromethyl,            pentafluoroethyl or trifluoromethoxymethyl,        -   R^(10A) and R^(10B) independently represent hydrogen or            methyl,    -   Ar² is phenyl,        -   where phenyl may be mono- to trisubstituted, identically or            differently, by fluorine, chlorine, (C₁-C₃)-alkyl,            difluoromethoxymethyl, trifluoromethoxymethyl and/or            trifluoromethyl,    -   or    -   is a 7- to 10-membered bicyclic or tricyclic carbocycle,    -   where the 7- to 10-membered bicyclic or tricyclic carbocycle may        be up to trisubstituted, identically or differently, by        (C₁-C₃)-alkyl and trifluoromethyl, and additionally up to        tetrasubstituted by fluorine,

-   Ar¹ is a group of the formula

-   -   in which    -   ** marks the bonding site to the nitrogen atom,    -   R^(3A) is fluorine, chlorine or trifluoromethyl,    -   R^(3B) is hydrogen or fluorine    -   and    -   R^(3C) is hydrogen, fluorine or chlorine        and the N-oxides, salts, solvates, salts of the N-oxides and        solvates of the N-oxides or salts thereof.

Preference is given in the context of the present invention to compoundsof the formula (I)

in which

-   R¹ is NR⁴R⁵,    -   in which    -   R⁴ is hydrogen or methyl,    -   and    -   R⁵ is (C₁-C₄)-alkyl or methylsulphonyl,        -   where (C₁-C₄)-alkyl may be up to disubstituted by hydroxyl            and additionally up to trisubstituted by fluorine,    -   or    -   R⁴ and R⁵ together with the nitrogen atom to which they are        bonded form a saturated or partially unsaturated, 4- to        6-membered monocyclic or 6- to 10-membered bicyclic heterocycle        which may contain one or two further heteroatoms from the group        of N, O, S, SO and SO₂ as ring member,        -   where the 4- to 6-membered monocyclic and the 6- to            10-membered bicyclic heterocycle may each be substituted by            1 to 5 substituents independently selected from the group of            (C₁-C₃)alkyl, difluoromethyl, trifluoromethyl,            hydroxymethyl, hydroxyethyl, hydroxyl, oxo, methoxy,            difluoromethoxy, trifluoromethoxy, methoxymethyl, cyano,            methoxycarbonyl, aminocarbonyl and            monomethylaminocarbonyloxy, and additionally up to            tetrasubstituted by fluorine,-   R² is a group of the formula

-   -   in which    -   * marks the bonding site to the nitrogen atom of the amide        moiety,    -   R^(6A) is hydrogen or methyl,    -   R^(6B) is hydrogen, (C₁-C₄)-alkyl, cyclopropyl, trifluoromethyl        or trifluoromethoxymethyl,    -   R⁷ is (C₁-C₄)-alkyl, cyclopropyl or cyclobutyl,        -   where (C₁-C₄)-alkyl may be up to pentasubstituted by            fluorine,    -   Y¹ is —(CH₂)_(k)—, —CF₂—, —O—CH₂—, —CH₂—O— or —CH₂—O—CH₂—,        -   in which        -   k is 0, 1, 2 or 3,    -   R⁸ is methyl, trifluoromethyl or 2,2,2-trifluoroethyl,    -   L¹ is a bond or a group of the formula —CR^(9A)R^(9B)—,        -   in which        -   R^(9A) represents hydrogen or methyl,        -   R^(9B) represents hydrogen, methyl, trifluoromethyl or            trifluoromethoxymethyl,    -   Ar² is phenyl,        -   which may be mono- or disubstituted, identically or            differently, by fluorine, chlorine, methyl and/or            trifluoromethyl,    -   R¹¹, R¹² and R²³ are each independently hydrogen, fluorine,        methyl, ethyl or trifluoroethyl,    -   n is the number 1 or 2,    -   where, if one of the substituents R¹¹, R¹² or R²³ occurs twice        in each case, its definitions may independently be the same or        different,

-   Ar¹ is a group of the formula

-   -   in which    -   ** marks the bonding site to the nitrogen atom,    -   R^(3A) is fluorine, chlorine or trifluoromethyl,    -   R^(3B) is hydrogen or fluorine    -   and    -   R^(3C) is hydrogen, fluorine or chlorine,        and the salts, solvates and solvates of the salts thereof.

Preference is given in the context of the present invention to compoundsof the formula (I) in which

-   R¹ is NR⁴R⁵,    -   in which    -   R⁴ is hydrogen or methyl,    -   and    -   R⁵ is (C₁-C₄)-alkyl or methylsulphonyl,        -   where (C₁-C₄)-alkyl may be substituted by hydroxyl and            additionally up to trisubstituted by fluorine,    -   or    -   R⁴ and R⁵ together with the nitrogen atom to which they are        bonded form a saturated 4- to 6-membered monocyclic or 6- to        10-membered bicyclic heterocycle which may contain one further        heteroatom from the group of N, O, S, SO and SO₂ as ring member,        -   where the 4- to 6-membered monocyclic and the 6- to            10-membered bicyclic heterocycle may each be substituted by            1 to 4 substituents independently selected from the group of            (C₁-C₃)alkyl, difluoromethyl, trifluoromethyl,            hydroxymethyl, hydroxyethyl, hydroxyl, oxo, methoxy,            difluoromethoxy, trifluoromethoxy, methoxymethyl, cyano,            methoxycarbonyl, aminocarbonyl and            monomethylaminocarbonyloxy, and additionally up to            tetrasubstituted by fluorine,-   R² is tert-butyl    -   or    -   is a group of the formula

-   -   in which    -   * marks the bonding site to the nitrogen atom of the amide        moiety,    -   R^(6A) is hydrogen or methyl,    -   R^(6B) is hydrogen, trifluoromethyl or trifluoromethoxymethyl,    -   R⁷ is (C₁-C₄)-alkyl or cyclopropyl,        -   where (C₁-C₄)-alkyl may be up to pentasubstituted by            fluorine,    -   Y¹ is —(CH₂)_(k)—, —O—CH₂—, —CH₂—O— or —CH₂—O—CH₂—,        -   in which        -   k is 1, 2 or 3,    -   R⁸ is methyl or trifluoromethyl,    -   L¹ is a bond or a group of the formula —CR^(9A)R^(9B)—,        -   in which        -   R^(9A) represents hydrogen or methyl,        -   R^(9B) represents hydrogen, methyl, trifluoromethyl or            trifluoromethoxymethyl,    -   Ar² is phenyl,        -   which may be mono- or disubstituted, identically or            differently, by fluorine, chlorine, methyl and/or            trifluoromethyl,    -   R¹¹ and R¹² are independently hydrogen, fluorine, methyl, ethyl        or trifluoromethyl,    -   n is the number 1 or 2,    -   where, if the substituent R¹² occurs twice, its definitions may        be the same or different,

-   Ar¹ is a group of the formula

-   -   in which    -   ** marks the bonding site to the nitrogen atom,    -   R^(3A) is fluorine, chlorine or trifluoromethyl,    -   R^(3B) is hydrogen or fluorine    -   and    -   R^(3C) is hydrogen, fluorine or chlorine        and the salts, solvates and solvates of the salts thereof.

A particular embodiment of the present invention encompasses compoundsof the formula (I) in which R¹ is a group of the formula

in which

-   marks the bonding site to the carbon atom of the pyridine ring,-   Y² and Y³ are independently a bond, —CH₂— or —(CH₂)₂—,-   Y⁴ is —(CH₂)₂—, —(CH₂)₃— or —CH₂—O—CH₂—,-   Y⁵ is —CF₂—,-   X¹, X³ and X⁴ are independently —O— or —NH—,-   X² is —O— or —NR¹⁴    -   in which    -   R¹⁴ is hydrogen, (C₁-C₃)-alkoxycarbonyl or aminocarbonyl,-   X⁵ is S(O)_(t),    -   in which    -   t is 0, 1 or 2,-   the ring Q₁ together with the atoms to which it is bonded forms a    three-membered saturated carbocycle,    -   where the three-membered saturated carbocycle may be        monosubstituted by hydroxyl or hydroxymethyl or up to        disubstituted by fluorine,    -   or is a group of the formula

-   -   in which    -   #¹ and #² mark the bonding site to the carbon atom of the        pyrrolidine ring,

-   R¹³ is fluorine, (C₁-C₃)-alkyl, difluoromethyl, trifluoromethyl,    hydroxyl, hydroxymethyl, hydroxyethyl, methoxy, difluoromethoxy,    trifluoromethoxy, methoxymethyl, cyano, methoxycarbonyl or    monomethylaminocarbonyloxy,

-   p is the number 0, 1, 2, 3 or 4,    where, in the case that the substituents R^(13D), R^(13E) and    R^(13F) occur more than once, the definitions thereof may each be    the same or different.

Preference is given in the context of the present invention to compoundsof the formula (I) in which

-   R¹ is NR⁴R⁵,    -   in which    -   R⁴ is hydrogen or methyl,    -   and    -   R⁵ is methyl, isopropyl, 2,2-difluoroethyl,        2,2,2-trifluoroethyl, 2-hydroxyethyl or 2-hydroxypropyl,    -   or    -   is a 4- to 6-membered monocyclic or 6- to 8-membered bicyclic        heterocycle which is bonded via a nitrogen atom and is of the        formula

-   -   in which    -   *** marks the bonding site to the carbon atom of the pyridine        ring,    -   the ring Q₁ is a group of the formula

-   -   -   in which        -   #¹ and #² mark the bonding site to the carbon atom of the            pyrrolidine ring,        -   and        -   Y⁷ is —CF₂— or —CHR¹⁵—,            -   in which            -   R¹⁵ represents methoxymethyl,        -   and        -   R¹⁶ is hydroxyl,

    -   R^(13A) is fluorine, hydroxyl, hydroxymethyl, methyl,        trifluoromethyl or methoxy,

    -   R^(13D) is hydrogen, fluorine, methyl, hydroxyl, hydroxymethyl,        methoxy or difluoromethoxy,

    -   R^(13E) is hydrogen, fluorine, methyl, hydroxyl, hydroxymethyl        or methoxy,

    -   R^(13F) is fluorine, methyl, hydroxyl, hydroxymethyl or cyano,

    -   R^(13G) is fluorine or hydroxyl,

    -   R^(13H) is hydrogen, methyl, hydroxymethyl, aminocarbonyl or        methoxycarbonyl,

    -   R^(13J) is oxo, hydroxymethyl or difluoromethyl,

    -   R^(13K) is hydrogen, methyl or 2-hydroxyethyl,

    -   R^(13L) is hydrogen or methyl,

    -   R^(13M) is ethyl, 2-hydroxyethyl or cyano,

    -   R^(13N) is hydrogen or ethyl,

    -   R^(13O) is hydrogen or hydroxyl,

    -   R¹⁴ is methyl, methoxycarbonyl or aminocarbonyl,

    -   q is the number 0, 1 or 2,

    -   r is the number 0, 1, 2 or 3,

    -   s is the number 0 or 1,

    -   t is the number 0, 1, 2, 3 or 4,

    -   where, in the case that the substituents R^(13A), R^(13D),        R^(13E), R^(13F), R^(13G), R^(13J) and R^(13L) occur more than        once, the definitions thereof may each be the same or different,

-   R² is a group of the formula

-   -   in which    -   * marks the bonding site to the nitrogen atom of the amide        moiety,    -   R^(6A) is hydrogen or methyl,    -   R^(6B) is methyl, ethyl, cyclopropyl, trifluoromethyl or        trifluoromethoxymethyl,    -   R⁷ is methyl, ethyl, n-propyl, isopropyl, tert-butyl,        2-methylprop-1-yl, trifluoromethyl, difluoromethyl,        pentafluoroethyl, 2,2,2-trifluoroethyl or cyclopropyl,    -   R⁸ is 2,2,2-trifluoroethyl,    -   L¹ is a bond or a group of the formula —CR^(9A)R^(9B),        -   in which        -   R^(9A) represents hydrogen or methyl,        -   R^(9B) represents hydrogen, methyl, trifluoromethyl or            trifluoromethoxymethyl,    -   Ar² is phenyl,        -   which may be mono- or disubstituted, identically or            differently, by fluorine, chlorine, methyl and/or            trifluoromethyl,    -   R¹¹ is hydrogen, fluorine or methyl,    -   R⁴ is hydrogen, fluorine, methyl, ethyl or trifluoromethyl,    -   R^(12B) is hydrogen or fluorine,    -   R²³ is hydrogen, fluorine or trifluoromethyl,

-   and

-   Ar¹ is a group of the formula

-   -   in which    -   ** marks the bonding site to the nitrogen atom,    -   R^(3A) is fluorine or chlorine,    -   R^(3B) is hydrogen or fluorine,    -   and    -   R^(3C) is hydrogen, fluorine or chlorine        and the salts, solvates and solvates of the salts thereof.

In the context of the present invention, particular preference is givento compounds of the formula (I) in which

-   R¹ is a group of the formula

-   -   in which    -   *** marks the bonding site to the carbon atom of the pyridine        ring,    -   R^(13DA) is hydrogen or methyl,    -   R^(13EA) is hydroxyl or hydroxymethyl,    -   R^(13EB) is methyl or hydroxymethyl,    -   R^(13EC) is hydrogen or methyl,    -   R^(13LA) is hydrogen or methyl,

-   R² is a group of the formula

-   -   in which    -   * marks the bonding site to the nitrogen atom of the amide        moiety,    -   R^(6B) is trifluoromethoxymethyl,    -   R^(7A) is methyl, ethyl, trifluoromethyl or cyclopropyl,    -   R^(7B) is trifluoromethyl, difluoromethyl or        2,2,2-trifluoroethyl,    -   R^(7C) is methyl or ethyl,    -   R¹⁹ is chlorine,

-   and

-   Ar¹ is a group of the formula

-   -   in which    -   ** marks the bonding site to the nitrogen atom,    -   R^(3A) is fluorine or chlorine, and    -   R^(3C) is hydrogen or fluorine,        and the salts, solvates and solvates of the salts thereof.

In the context of the present invention, very particular preference isgiven to compounds of the formula (I) in which

-   R¹ is a group of the formula

-   -   in which    -   *** marks the bonding site to the carbon atom of the pyridine        ring,

-   R² is a group of the formula

-   -   in which    -   *marks the bonding site to the nitrogen atom of the amide        moiety,    -   R^(7A) is ethyl, trifluoromethyl or cyclopropyl,    -   R^(7B) is trifluoromethyl,    -   R^(7C) is methyl or ethyl,

-   and

-   Ar¹ is a group of the formula

-   -   in which    -   ** marks the bonding site to the nitrogen atom,        and the salts, solvates and solvates of the salts thereof.

Preference is given in the context of the present invention to compoundsof the formula (I) in which

-   R¹ is NR⁴R⁵,    -   in which    -   R⁴ is hydrogen or methyl,    -   and    -   R⁵ is methyl, isopropyl, 2,2-difluoroethyl or        2,2,2-trifluoroethyl,    -   or    -   is a 4- to 6-membered monocyclic or 6- to 8-membered bicyclic        heterocycle which is bonded via a nitrogen atom and is of the        formula

-   -   in which    -   *** marks the bonding site to the carbon atom of the pyridine        ring,    -   Y² is —CH₂—,    -   Y⁶ is —CH₂— or —CF₂—,    -   the ring Q₁ is a group of the formula

-   -   -   in which        -   #¹ and #² mark the bonding site to the carbon atom of the            pyrrolidine ring,        -   Y⁷ is —CH₂— or —CHR¹⁵⁻,            -   in which            -   R¹⁵ represents methoxymethyl,        -   and        -   R¹⁶ is hydroxyl,

    -   R^(13A) is fluorine, hydroxyl or hydroxymethyl,

    -   R^(13B) is hydroxyl,

    -   R^(13C) is trifluoromethyl,

    -   R^(13D) is fluorine, methyl, hydroxyl, hydroxymethyl, methoxy or        difluoromethoxy,

    -   R^(13E) is fluorine, methyl, hydroxyl or methoxy,

    -   R^(13F) is fluorine, methyl, hydroxyl, hydroxymethyl or cyano,

    -   R^(13G) is hydroxyl,

    -   R^(13H) is hydrogen, methyl, hydroxymethyl or methoxycarbonyl,

    -   R^(13J) is hydroxymethyl or difluoromethyl,

    -   R¹⁴ is methoxycarbonyl or aminocarbonyl,

    -   q is the number 0, 1 or 2,

    -   r is the number 0, 1, 2 or 3,

    -   s is the number 0 or 1,

    -   where, in the case that the substituents R^(13D), R^(13E) and        R^(13F) occur more than once, the definitions thereof may each        be the same or different,

-   R² is tert-butyl    -   or    -   is a group of the formula

-   -   in which    -   * marks the bonding site to the nitrogen atom of the amide        moiety,    -   R^(6A) is hydrogen or methyl,    -   R^(6B) is trifluoromethyl or trifluoromethoxymethyl,    -   R⁷ is methyl, ethyl, n-propyl, isopropyl, tert-butyl,        2-methylprop-1-yl, trifluoromethyl or cyclopropyl,    -   L¹ is a bond or a group of the formula —CR^(9A)R^(9B)—,        -   in which        -   R^(9A) represents hydrogen or methyl,        -   R^(9B) represents hydrogen, methyl, trifluoromethyl or            trifluoromethoxymethyl,    -   Ar² is phenyl,        -   which may be mono- or disubstituted, identically or            differently, by fluorine, chlorine, methyl and/or            trifluoromethyl,    -   R¹¹ is hydrogen, fluorine or methyl,    -   R^(12A) is hydrogen, fluorine, methyl, ethyl or trifluoromethyl,    -   R^(12B) is hydrogen or fluorine,

-   and

-   Ar¹ is a group of the formula

-   -   in which    -   ** marks the bonding site to the nitrogen atom,    -   R^(3A) is fluorine or chlorine,    -   and    -   R^(3B) is hydrogen or fluorine,        and the salts, solvates and solvates of the salts thereof.

Preference is given in the context of the present invention to compoundsof the formula (I) in which

-   R¹ is a group of the formula

-   -   in which    -   *** marks the bonding site to the carbon atom of the pyridine        ring,

-   R² is a group of the formula

-   -   in which    -   * marks the bonding site to the nitrogen atom of the amide        moiety,    -   R⁷ is ethyl or cyclopropyl,    -   R^(17A) is fluorine or chlorine,    -   R^(18A) is fluorine,    -   R^(17B) and R^(18B) are each chlorine,    -   R¹⁹ is fluorine or chlorine,    -   R²⁰ is fluorine,

-   and

-   Ar¹ is a group of the formula

-   -   in which    -   ** marks the bonding site to the nitrogen atom,    -   R^(3A) is fluorine or chlorine,        and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention encompassescompounds of the formula (I) in which

-   R² is tert-butyl    -   or    -   is a group of the formula

-   -   in which    -   *marks the bonding site to the nitrogen atom of the amide        moiety,    -   R^(6A) is hydrogen or methyl,    -   R^(6B) is trifluoromethyl or trifluoromethoxymethyl,    -   R⁷ is methyl, ethyl, n-propyl, isopropyl, tert-butyl,        2-methylprop-1-yl, trifluoromethyl or cyclopropyl,    -   L¹ is a bond or a group of the formula —CR^(9A)R^(9B)—,        -   in which        -   R^(9A) represents hydrogen or methyl,        -   R^(9B) represents hydrogen, methyl, trifluoromethyl or            trifluoromethoxymethyl,    -   Ar² is phenyl,        -   which may be mono- or disubstituted, identically or            differently, by fluorine, chlorine, methyl and/or            trifluoromethyl,            and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention encompassescompounds of the formula (I) in which

-   R² is a group of the formula

-   -   in which    -   * marks the bonding site to the nitrogen atom of the amide        moiety,    -   R^(6A) is hydrogen or methyl,    -   R^(6B) is methyl, ethyl, cyclopropyl, trifluoromethyl or        trifluoromethoxymethyl,    -   R⁷ is methyl, ethyl, n-propyl, isopropyl, tert-butyl,        2-methylprop-1-yl, trifluoromethyl, difluoromethyl,        pentafluoroethyl, 2,2,2-trifluoroethyl or cyclopropyl,    -   R⁸ is 2,2,2-trifluoroethyl,    -   R²³ is hydrogen, fluorine or trifluoromethyl,        and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention encompassescompounds of the formula (I) in which

-   R² is a group of the formula

*-L¹-Ar²

-   -   in which    -   * marks the bonding site to the nitrogen atom of the amide        moiety,    -   L¹ is a bond or a group of the formula —CR^(9A)R^(9B)—,        -   in which        -   R^(9A) represents hydrogen,        -   R^(9B) represents hydrogen, methyl, trifluoromethyl or            trifluoromethoxymethyl,    -   Ar² is phenyl        -   or        -   a group of the formula

-   -   -   in which        -   #³ marks the bonding site        -   R¹⁷ and R¹⁹ independently represent fluorine, chlorine,            methyl or trifluoromethyl,        -   R¹⁸, R²⁰ and R²¹ independently represent fluorine, chlorine            or methyl,            and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention encompassescompounds of the formula (I) in which

-   R² is a group of the formula

*-L¹-Ar²

-   -   in which    -   * marks the bonding site to the nitrogen atom of the amide        moiety,    -   L¹ is a bond or a group of the formula —CR^(9A)R^(9B)—,        -   in which        -   R^(9A) represents hydrogen,        -   R^(9B) represents methyl, trifluoromethyl or            trifluoromethoxymethyl,            and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention encompassescompounds of the formula (I) in which

-   R² is a group of the formula

-   -   in which    -   * marks the bonding site to the nitrogen atom of the amide        moiety,    -   R⁷ is ethyl or cyclopropyl,    -   R^(17A) is fluorine or chlorine,    -   R^(18A) is fluorine,    -   R^(17B) and R^(18B) are each chlorine,    -   R¹⁹ is fluorine or chlorine,    -   and    -   R²⁰ is fluorine,        and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention encompassescompounds of the formula (I) in which

-   R² is a group of the formula

-   -   in which    -   *marks the bonding site to the nitrogen atom of the amide        moiety,    -   R^(6B) is trifluoromethoxymethyl,    -   R^(7A) is methyl, ethyl, trifluoromethyl or cyclopropyl,    -   R^(7B) is trifluoromethyl, difluoromethyl or        2,2,2-trifluoroethyl,    -   R^(7C) is methyl or ethyl,    -   R¹⁹ is chlorine,        and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention encompassescompounds of the formula (I) in which

-   R² is a group of the formula

-   -   in which    -   * marks the bonding site to the nitrogen atom of the amide        moiety,    -   R^(7A) is ethyl, trifluoromethyl or cyclopropyl,    -   R^(7B) is trifluoromethyl,    -   R^(7C) is methyl or ethyl,        and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention encompassescompounds of the formula (I) in which

-   R² is (2S)-1,1,1-trifluorobutan-2-yl of the formula

-   -   in which    -   * marks the bonding site to the nitrogen atom of the amide        moiety,        and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention encompassescompounds of the formula (I) in which

-   R² is (1S)-1-cyclopropyl-2,2,2-trifluoroethyl

-   -   in which    -   * marks the bonding site to the nitrogen atom of the amide        moiety,        and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention encompassescompounds of the formula (I) in which

-   R² is 1,1,1,3,3,3-hexafluoropropan-2-yl,    and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention encompassescompounds of the formula (I) in which

R² is 3,3,4,4,4-pentafluorobutan-2-yl,and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention encompassescompounds of the formula (I) in which

-   R² is 1,1,1,2,2-pentafluoropentan-3-yl,    and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention encompassescompounds of the formula (I) in which

-   R² is 1,1,1-trifluoro-2-methylpropan-2-yl,    and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention encompassescompounds of the formula (I) in which

-   R² is a group of the formula

-   -   in which    -   * marks the bonding site to the nitrogen atom of the amide        moiety,    -   R⁷ is ethyl or cyclopropyl,        and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention encompassescompounds of the formula (I) in which

-   Ar¹ is a group of the formula

-   -   in which    -   ** marks the bonding site to the nitrogen atom,    -   R^(3A) is fluorine or chlorine, and    -   R^(3C) is hydrogen or fluorine    -   and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention encompassescompounds of the formula (I) in which

-   Ar¹ is a group of the formula

-   -   in which    -   ** marks the bonding site to the nitrogen atom,    -   and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention encompassescompounds of the formula (I) in which

-   Ar¹ is a group of the formula

-   -   in which    -   ** marks the bonding site to the nitrogen atom,    -   R^(3A) is fluorine or chlorine,        and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention encompassescompounds of the formula (I) in which

-   Ar¹ is a group of the formula

-   -   in which    -   ** marks the bonding site to the nitrogen atom,    -   and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention encompassescompounds of the formula (I) in which

-   Ar¹ is a group of the formula

-   -   in which    -   ** marks the bonding site to the nitrogen atom,    -   and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention encompassescompounds of the formula (I) in which

-   R¹ is NR⁴R⁵,    -   in which    -   R⁴ is hydrogen or methyl,    -   and    -   R⁵ is methyl, isopropyl, 2,2-difluoroethyl or        2,2,2-trifluoroethyl,        and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention encompassescompounds of the formula (I) in which

R¹ is a group of the formula

-   -   in which    -   *** marks the bonding site to the carbon atom of the pyridine        ring,        and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention encompassescompounds of the formula (I) in which

-   R¹ is a group of the formula

-   -   in which    -   *** marks the bonding site to the carbon atom of the pyridine        ring,        and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention encompassescompounds of the formula (I) in which

-   R¹ is trans-(3R,4R)-3,4-dihydroxypyrrolidin-1-yl of the formula

-   -   in which    -   *** marks the bonding site to the carbon atom of the pyridine        ring,        and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention encompassescompounds of the formula (I) in which

-   R¹ is cis-(R,S)-3,4-dihydroxypyrrolidin-1-yl of the formula

-   -   in which    -   *** marks the bonding site to the carbon atom of the pyridine        ring,        and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention encompassescompounds of the formula (I) in which

-   R¹ is a group of the formula

-   -   in which    -   *** marks the bonding site to the carbon atom of the pyridine        ring,        and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention encompassescompounds of the formula (I) in which

-   R¹ is (4S)-4-hydroxy-2-oxopyrrolidin-1-yl of the formula

-   -   in which    -   *** marks the bonding site to the carbon atom of the pyridine        ring,        and the salts, solvates and solvates of the salts thereof.

Irrespective of the particular combinations of the radicals specified,the individual radical definitions specified in the particularcombinations or preferred combinations of radicals are also replaced asdesired by radical definitions of other combinations.

Very particular preference is given to combinations of two or more ofthe abovementioned preferred ranges and embodiments.

The radical definitions specified as preferred, particularly preferredand very particularly preferred apply both to the compounds of theformula (I) and correspondingly toward all intermediates.

The invention further provides a process for preparing compounds of theformula (I) according to the invention, characterized in that

[A] a compound of the formula (II)

-   -   in which R² and Ar¹ have the definitions given above    -   and    -   Hal is fluorine, chlorine, bromine or iodine, preferably        chlorine,    -   is reacted with a compound of the formula (III)

R¹—H  (III)

-   -   in which R¹ has the definition given above    -   to give the inventive carboxamide of the formula (I)

-   -   in which R¹, R² and Ar¹ have the definitions given above,        or        [B] a compound of the formula (IV)

-   -   in which R¹ and Ar¹ have the definitions given above,    -   is reacted with a compound of the formula (V)

R²—NH₂  (V),

-   -   in which R² has the definition given above,    -   to give the inventive carboxamide of the formula (I)

-   -   in which R¹, R² and Ar¹ have the definitions given above,        and, if appropriate, the compounds of the formula (I) thus        obtained are separated into their enantiomers and/or        diastereomers and/or converted with the appropriate (i) solvents        and/or (ii) bases or acids to their solvates, salts and/or        solvates of the salts.

The reaction (II)+(III)→(I) can be effected via a nucleophilicsubstitution reaction or via a transition metal-mediated couplingreaction.

The nucleophilic substitution reaction is preferably conducted in thepresence of a base. Suitable bases for the process step (II)+(III)→(I)are the customary inorganic or organic bases. These preferably includealkali metal hydroxides, for example lithium hydroxide, sodium hydroxideor potassium hydroxide, alkali metal or alkaline earth metal carbonatessuch as lithium carbonate, sodium carbonate, potassium carbonate orcaesium carbonate, alkali metal alkoxides such as sodium methoxide orpotassium methoxide, sodium ethoxide or potassium ethoxide or lithiumtert-butoxide, sodium tert-butoxide or potassium tert-butoxide, alkalimetal hydrides such as sodium hydride or potassium hydride, amides suchas sodium amide, lithium bis(trimethylsilyl)amide or potassiumbis(trimethylsilyl)amide or lithium diisopropylamide, or organic aminessuch as N,N-diisopropylethylamine (DIPEA),1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Preference is given to usingN,N-diisopropylethylamine (DIPEA). The reaction is effected generallywithin a temperature range from 0° C. to +100° C., preferably at +23° C.to +80° C.

Inert solvents for the process step (II)+(III)→(I) are, for example,ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethylether or diethylene glycol dimethyl ether, hydrocarbons such as benzene,toluene, xylene, hexane, cyclohexane or mineral oil fractions,halohydrocarbons such as dichloromethane, trichloromethane,tetrachloromethane, 1,2-dichloroethane, trichloroethylene orchlorobenzene, or other solvents such as acetone, ethyl acetate,acetonitrile, pyridine, dimethyl sulphoxide, N,N-dimethylformamide(DMF), N,N′-dimethylpropyleneurea (DMPU) or N-methylpyrrolidone (NMP).It is likewise possible to use mixtures of the solvents mentioned.Preference is given to using dimethylformamide (DMF) orN-methylpyrrolidone (NMP).

The transition metal-mediated coupling reaction for the process step(II)+(III)→(I), in a preferred embodiment, is conducted in the presenceof a palladium catalyst. Suitable palladium catalysts are, for example,palladium(II) acetate, palladium(II) chloride,bis(triphenylphosphine)palladium(II) chloride,bis(acetonitrile)palladium(II) chloride,tetrakis(triphenylphosphine)palladium(0),bis(dibenzylideneacetone)palladium(0),tris(dibenzylideneacetone)palladium(0) or[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride, optionallyin combination with a suitable phosphine ligand, for exampletriphenylphosphine, tritert-butylphosphine,2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-Phos),2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (S-Phos),1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene (Q-Phos),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP),2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl or2-di-tert-butylphosphino-2′-(N,N-dimethylamino)biphenyl.

The palladium-catalysed coupling reaction (II)+(III)→(I) is generallyconducted in the presence of a base. Suitable bases are especiallyalkali metal carbonates such as sodium carbonate, potassium carbonate orcaesium carbonate, alkali metal phosphates such as sodium phosphate orpotassium phosphate, alkali metal fluorides such as potassium fluorideor caesium chloride, or alkali metal tert-butoxides such as sodiumtert-butoxide or potassium tert-butoxide. The reaction is effected in aninert solvent, for example toluene, 1,2-dimethoxyethane,tetrahydrofuran, 1,4-dioxane, dimethyl sulphoxide (DMSO),N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA) or mixturesthereof, within a temperature range from +80° C. to +200° C., preferablyat +80° C. to +150° C., where heating by means of microwave apparatusmay be advantageous.

Preference is given to using, for this coupling reaction, acatalystligand/base system consisting of palladium(II) acetate,4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) and caesiumcarbonate or potassium carbonate, and 1,4-dioxane as solvent.

The coupling reaction (II)+(III)→(I) may, in a further preferredembodiment, also be conducted with the aid of a copper(I) catalyst, suchas copper(I) oxide, bromide or iodide, in the presence of a copperligand such as trans-N,N′-dimethyl-1,2-cyclohexanediamine,8-hydroxyquinoline or 1,10-phenanthroline, and of an inorganic ororganic carbonate base, such as potassium carbonate, caesium carbonateor bis(tetraethylammonium) carbonate. Suitable inert solvents for thisreaction are especially toluene, xylene, 1,4-dioxane, acetonitrile,dimethyl sulphoxide (DMSO), N,N-dimethylformamide (DMF) or mixturesthereof, optionally with addition of water. Preference is given to usinga system consisting of copper(I) iodide,trans-N,N′-dimethyl-1,2-cyclohexanediamine and potassium carbonate indimethylformamide. The reaction is effected generally within atemperature range from +50° C. to +200° C., preferably at +60° C. to+150° C.

The coupling reaction (IV)+(V)→(I) [amide formation] can be effectedeither by a direct route with the aid of a condensing or activatingagent or via the intermediate stage of a carbonyl chloride, carboxylicester or carbonyl imidazolide obtainable from (IV).

Suitable condensing or activating agents are, for example, carbodiimidessuch as N,N′-diethyl-, N,N′-dipropyl-, N,N′-diisopropyl-,N,N′-dicyclohexylcarbodiimide (DCC) orN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC),phosgene derivatives such as N,N′-carbonyldiimidazole (CDI), isopropylchloroformate or isobutyl chloroformate, 1,2-oxazolium compounds such as2-ethyl-5-phenyl-1,2-oxazolium 3-sulphate or2-tert-butyl-5-methylisoxazolium perchlorate, acylamino compounds suchas 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, α-chloroenamines suchas 1-chloro-N,N,2-trimethylprop-1-en-1-amine, 1,3,5-triazine derivativessuch as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholiniumchloride, phosphorus compounds such as n-propanephosphonic anhydride(PPA), diethyl cyanophosphonate, diphenylphosphoryl azide (DPPA),bis(2-oxo-3-oxazolidinyl)phosphoryl chloride,benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphateor benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate(PyBOP), or uronium compounds such asO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU),O-(1H-6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (TCTU),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) or2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethyluronium tetrafluoroborate(TPTU), optionally in combination with further auxiliaries such as1-hydroxybenzotriazole (HOBt) or N-hydroxysuccinimide (HOSu), and also,as bases, alkali metal carbonates, e.g. sodium carbonate or potassiumcarbonate, or tertiary amine bases such as triethylamine,N-methylmorpholine (NMM), N-methylpiperidine (NMP),N,N-diisopropylethylamine (DIPEA), pyridine or4-N,N-dimethylaminopyridine (DMAP). Condensing or activating agents usedwith preference areO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) in combination with N,N-diisopropylethylamine(DIPEA), and isopropyl chloroformate in combination withN-methylmorpholine (NMM) andbenzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate(PyBOP) in combination with N,N-diisopropylethylamine (DIPEA).

In the case of a two-stage reaction regime via the carbonyl chlorides orcarbonyl imidazolides obtainable from (IV), the coupling with the aminecomponent (V) is conducted in the presence of a customary base, forexample sodium carbonate or potassium carbonate, triethylamine, DIPEA,N-methylmorpholine (NMM), N-methylpiperidine (NMP), pyridine,2,6-dimethylpyridine, 4-N,N-dimethylaminopyridine (DMAP),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),1,5-diazabicyclo[4.3.0]non-5-ene (DBN), sodium methoxide or potassiummethoxide, sodium ethoxide or potassium ethoxide, sodium tert-butoxideor potassium tert-butoxide, or sodium hydride or potassium hydride.

The carbonyl imidazolides themselves are obtainable by known methods byreaction of (II) with N,N′-carbonyldiimidazole (CDI) at elevatedtemperature (+60° C. to +150° C.) in a correspondingly relativelyhigh-boiling solvent such as N,N-dimethylformamide (DMF). Thepreparation of the carbonyl chlorides is accomplished in a customarymanner by treating (II) with thionyl chloride or oxalyl chloride in aninert solvent such as dichloromethane or THF.

Inert solvents for the coupling reactions mentioned are—according to themethod used—for example ethers such as diethyl ether, diisopropyl ether,methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane,1,2-dimethoxyethane or bis(2-methoxyethyl) ether, hydrocarbons such asbenzene, toluene, xylene, pentane, hexane or cyclohexane,halohydrocarbons such as dichloromethane, trichloromethane, carbontetrachloride, 1,2-dichloroethane, trichloroethylene or chlorobenzene,or polar aprotic solvents such as acetone, methyl ethyl ketone, ethylacetate, acetonitrile, butyronitrile, pyridine, dimethyl sulphoxide(DMSO), N,N-dimethylformamide (DMF), N,N′-dimethylpropyleneurea (DMPU)or N-methylpyrrolidinone (NMP). It is also possible to use mixtures ofsuch solvents. Preference is given to using N,N-dimethylformamide (DMF).The couplings are generally conducted within a temperature range from 0°C. to +130° C., preferably at +20° C. to +30° C.

The preferred coupling method is the direct reaction of (II) with theamine compound (III) with the aid of a condensing or activating agent.

In the case of a two-stage reaction regime via the carboxylic estersobtainable from (IV), the coupling can be conducted with an activatedamine component (V). The amine component (V) is preferably activated bythe reaction with trimethylaluminium (cf. Tetrahedron Lett. 1977, 18,4171-4174). Preference is given to using dichloromethane (DCM) as inertsolvent. The couplings are generally conducted within a temperaturerange from 0° C. to +130° C., preferably at room temperature.

The compounds of the formula (II) can be prepared by reacting acarboxylic acid compound of the formula (VI)

-   -   in which Hal and Ar¹ have the definitions given above    -   with a compound of the formula (V)

R²—NH₂  (V)

-   -   in which R² has the definition given above    -   to give the inventive carboxamide of the formula (II)

-   -   in which Hal, R¹, R² and Ar¹ have the definitions given above.

The coupling reaction (VI)+(V)→(II) [amide formation] can be effectedeither by a direct route with the aid of a condensing or activatingagent or via the intermediate stage of a carbonyl chloride, carboxylicester or carbonyl imidazolide obtainable from (VI), analogously to theconditions and reagents already described for the reaction (IV)+(V)→(I).

If HATU is used as activating agent in the coupling reaction to give(II), it is possible that either an individual defined product of thegeneral formula (II) is obtained, or else a mixture with a “HATUadduct”. A “HATU adduct” in the present context refers to a pseudohalidecompound where the Hal substituent in the general formula (II) isreplaced by the 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol group, alsoreferred to as 1-hydroxy-7-azabenzotriazole. Such a mixture of a halogencompound of the general formula (II) and a “HATU adduct” can likewise beused, analogously to the reaction described, as reactant for the furtherreaction (after (I) or (VIII)).

Depending on their respective substitution pattern, the compounds of theformula (IV) can be prepared by reacting either

[C] a compound of the formula (VII)

-   -   in which Hal and Ar¹ have the definitions given above    -   and    -   T is (C₁-C₄)-alkyl or benzyl,    -   in a first step with a compound of the formula (III)

R¹—H  (III)

-   -   in which R¹ has the definition given above    -   to give a compound of the formula (VIII)

-   -   in which T, R¹ and Ar¹ have the definitions given above,    -   and optionally, in a second step, detaching the ester radical T        to give the inventive carboxylic acid of the formula (IV)

-   -   in which R¹ and Ar¹ have the definitions given above        or        [D] a compound of the formula (VI)

-   -   in which Hal and Ar¹ have the definitions given above    -   with a compound of the formula (III)

R¹—H  (III)

-   -   in which R¹ has the definition given above    -   to give the inventive carboxylic acid of the formula (IV)

-   -   in which R¹ and Ar¹ have the definitions given above.

The reaction (VII)+(III)→(VIII) [route C] or the reaction(VI)+(III)→(IV) [route D] can be effected via a nucleophilicsubstitution reaction or a transition metal-mediated coupling reactionanalogously to the conditions already described for the reaction(II)+(III)→(I).

In a preferred embodiment, the reaction is conducted according to routeC as a nucleophilic substitution reaction in the presence of a base,preference being given to using N,N-diisopropylethylamine (DIPEA).Preference is given to using dimethylformamide (DMF),N-methylpyrrolidone (NMP) or acetonitrile as solvent.

In a preferred embodiment, the reaction is conducted according to routeD as a transition metal-mediated coupling reaction in the presence of asuitable palladium catalyst or copper(I) catalyst. Preference is givento using a system consisting of palladium(II) acetate in combinationwith 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), caesiumcarbonate or potassium carbonate and 1,4-dioxane as solvent, orpreference is likewise given to using a system consisting of copper(I)iodide, trans-N,N′-dimethyl-1,2-cyclohexanediamine and potassiumcarbonate in dimethylformamide as solvent.

The detachment of the ester group T in process step (VIII)→(IV) isconducted by customary methods, by treating the ester in an inertsolvent with an acid or a base, with conversion of the salt of thecarboxylic acid initially formed in the latter variant to the freecarboxylic acid by subsequent treatment with acid. In the case of thetert-butyl esters, the ester cleavage is preferably effected with anacid. Benzyl esters can alternatively also be cleaved by hydrogenation(hydrogenolysis) in the presence of a suitable catalyst, for examplepalladium on activated carbon.

Suitable solvents for these reactions are water and the organic solventscustomary for ester cleavage. These especially include alcohols such asmethanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol,ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane or1,2-dimethoxyethane, or other solvents such as dichloromethane,acetonitrile, N,N-dimethylformamide or dimethyl sulphoxide. It isequally possible to use mixtures of these solvents. In the case of abasic ester hydrolysis, preference is given to using mixtures of waterwith tetrahydrofuran.

Suitable bases for a hydrolysis reaction are the customary inorganicbases. These especially include alkali metal or alkaline earth metalhydroxides, for example lithium hydroxide, sodium hydroxide, potassiumhydroxide or barium hydroxide, or alkali metal or alkaline earth metalcarbonates, such as sodium carbonate, potassium carbonate or calciumcarbonate. Preference is given to using aqueous lithium hydroxidesolution or sodium hydroxide solution in a mixture with THF ascosolvent.

Suitable acids for the ester cleavage are generally sulphuric acid,hydrogen chloride/hydrochloric acid, hydrogen bromide/hydrobromic acid,phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulphonicacid, methanesulphonic acid or trifluoromethanesulphonic acid, ormixtures thereof, optionally with addition of water. Preference is givento using aqueous hydrochloric acid (18 percent) in awater/tetrahydrofuran mixture.

The ester cleavage is generally conducted within a temperature rangefrom −20° C. to +100° C., preferably at 23° C. to +120° C.

Depending on the particular substitution pattern, the compounds of theformula (VI) and of the formula (VIIIL) can be prepared by, in analogyto known processes (see, for example, EP 0607825 A1, p. 25-26), reactinga 2,6-dichloronicotinoylacrylate derivative of the formula (IX)

-   -   in which Hal and T have the definitions given above    -   and    -   X is a leaving group such as dimethylamino, methoxy or ethoxy,        and    -   in a first stage, preferably in the presence of a suitable base,        with an aniline compound of the formula (X)

Ar¹—NH₂  (X)

-   -   in which Ar¹ has the definitions given above    -   to give an intermediate of the formula (XI)

-   -   in which Hal, Ar¹ and T have the definitions given above,    -   and then reacting the latter in the presence of a suitable base        to give the ester compound of the formula (VII)

-   -   in which Hal, Ar¹ and T have the definition given above,    -   and then optionally converting the ester compound (VII) under        hydrolysis conditions in a further step to the carboxylic acid        compound (VI)

-   -   in which Hal and Ar¹ have the definitions given above    -   under the reaction conditions known in the literature.

The compounds of the formula (IX) are known from the literature (see,for example, EP 0607825 A1) or can be prepared in analogy to processesknown from the literature.

The compounds of the formulae (III), (V) and (X) are commerciallyavailable or described as such in the literature, or they can beprepared in a way obvious to the person skilled in the art, in analogyto methods published in the literature. Numerous detailed methods andliterature data for preparation of the respective starting materials canalso be found in the Experimental Part in the section relating to thepreparation of the starting compounds and intermediates.

The separation of stereoisomers (enantiomers and/or diastereomers) ofthe inventive compounds of the formula (I) can be achieved by customarymethods familiar to those skilled in the art. Preference is given toemploying chromatographic methods on achiral or chiral separation phasesfor this purpose.

Separation of the compounds according to the invention into thecorresponding enantiomers and/or diastereomers can, if appropriate, alsobe conducted at the early stage of the intermediates (II), (IV) or(VIII), which are then reacted further in separated form in accordancewith the reaction sequence described above. For such a separation of thestereoisomers of intermediates, preference is likewise given toemploying chromatographic methods on achiral or chiral separationphases. Alternatively, separation can also be effected viadiastereomeric salts of the carboxylic acids of the formula (IV) withchiral amine bases.

The preparation of the inventive compounds can be illustrated by way ofexample by the following reaction schemes:

Further inventive compounds of the formula (I) can, if appropriate, alsobe prepared by transformations of functional groups of individualradicals or substituents, especially those listed under R^(D) and R,proceeding from other compounds of the formula (I) or precursors thereofobtained by the above processes. These transformations are conducted bycustomary methods familiar to the person skilled in the art and include,for example, reactions such as nucleophilic or electrophilicsubstitution reactions, transition-metal-mediated coupling reactions,preparation and addition reactions of metal organyls (e.g. Grignardcompounds or lithium organyls), oxidation and reduction reactions,hydrogenation, halogenation (e.g. fluorination, bromination),dehalogenation, amination, alkylation and acylation, the formation ofcarboxylic esters, carboxamides and sulphonamides, ester cleavage andhydrolysis, and the introduction and removal of temporary protectinggroups.

The invention relates, in a further aspect, to intermediates of thegeneral formula (II)

-   -   in which R² and Ar¹ have the definitions given above for        compounds of the formula (I)    -   and    -   Hal is fluorine, chlorine, bromine or iodine, preferably        chlorine.

The invention relates, in a further aspect, to intermediates of thegeneral formula (IV)

-   -   in which R¹ and Ar¹ have the definitions given above for        compounds of the formula (I).

The invention relates, in a further aspect, to the use of a compound ofthe general formula (II)

-   -   in which R² and Ar¹ have the definitions given above for        compounds of the formula (I)    -   and    -   Hal is fluorine, chlorine, bromine or iodine, preferably        chlorine.    -   or    -   a compound of the general formula (IV)

-   -   -   in which R¹ and Ar¹ have the definitions given above for            compounds of the formula (I) for preparation of a compound            of the general formula (I) as defined above.

The compounds according to the invention have an unforeseeable usefulspectrum of pharmacological and pharmacokinetic activity.

They are therefore suitable for use as medicaments for treatment and/orprophylaxis of diseases in humans and animals. The compounds accordingto the invention have valuable pharmacological properties and can beused for treatment and/or prophylaxis of disorders in humans andanimals.

The compounds according to the invention are positive allostericmodulators of the muscarinic M2 receptor and are therefore suitable fortreatment and/or prevention of disorders and pathological processes,especially cardiovascular disorders and/or renal disorders, wherein theM2 receptor is involved in dysregulation of the autonomic nervous systemor an imbalance between the activity of the sympathetic andparasympathetic portion of the autonomic nervous system.

The present invention provides positive allosteric modulators of themuscarinic M2 receptor. Allosteric modulators have distinct differencesfrom conventional orthosteric ligands. The effect of an allostericmodulator is self-limiting when it stabilizes the binding of the agonistin high concentrations. Furthermore, the effect of an allostericmodulator can be displayed only in the presence of the endogenousligand. The allosteric modulator itself has no direct influence onreceptor activation. This gives rise to specificity of the allostericeffect in terms of space and time. The mutual influencing of allostericand orthosteric ligands in terms of affinity and intrinsic activity,which is referred to as cooperativity, is determined by both ligands. Inthe case of a positive allosteric modulator, the effects of theorthosteric ligand are enhanced (positive cooperativity). Because of itsability to modulate receptor combinations in the presence of anorthosteric ligand, allosteric ligands can bring about fine adjustmentof pharmacological effects.

In the context of the present invention, disorders of the cardiovascularsystem or cardiovascular disorders are understood to mean, for example,the following disorders: acute and chronic heart failure, arterialhypertension, coronary heart disease, stable and unstable anginapectoris, myocardial ischaemia, myocardial infarction, shock,atherosclerosis, cardiac hypertrophy, cardiac fibrosis, atrial andventricular arrhythmias, tachycardia, transitory and ischaemic attacks,stroke, pre-eclampsia, inflammatory cardiovascular disorders, peripheraland cardiac vascular disorders, peripheral perfusion disorders, arterialpulmonary hypertension, spasms of the coronary arteries and peripheralarteries, thromboses, thromboembolic disorders, oedema development, forexample pulmonary oedema, cerebral oedema, renal oedema or heartfailure-related oedema, and restenoses such as after thrombolysistreatments, percutaneous transluminal angioplasty (PTA), transluminalcoronary angioplasty (PTCA), heart transplants and bypass operations,and micro- and macrovascular damage (vasculitis), reperfusion damage,arterial and venous thromboses, microalbuminuria, myocardialinsufficiency, endothelial dysfunction, peripheral and cardiac vasculardisorders, peripheral perfusion disorders, heart failure-related oedema,elevated levels of fibrinogen and of low-density LDL and elevatedconcentrations of plasminogen activator/inhibitor 1 (PAI 1).

In the context of the present invention, the term “heart failure” alsoincludes more specific or related types of disease, such as acutelydecompensated heart failure, right heart failure, left heart failure,global failure, ischaemic cardiomyopathy, dilated cardiomyopathy,congenital heart defects, heart valve defects, heart failure associatedwith heart valve defects, mitral valve stenosis, mitral valveinsufficiency, aortic valve stenosis, aortic valve insufficiency,tricuspid stenosis, tricuspid insufficiency, pulmonary valve stenosis,pulmonary valve insufficiency, combined heart valve defects, myocardialinflammation (myocarditis), chronic myocarditis, acute myocarditis,viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy,cardiac storage disorders, and diastolic and systolic heart failure.

In the context of the present invention, the term atrial and ventriculararrhythmias also includes more specific or related types of disease,such as: atrial fibrillation, paroxysmal atrial fibrillation,intermittierent atrial fibrillation, permanent atrial fibrillation,atrial flutter, sinusoidal arrhythmia, sinusoidal tachycardia, passiveheterotopia, active heterotopia, escape systoles, extra systoles,impulse conduction disorders, sick sinus syndrome, hypersensitivecarotid sinus, tachycardias, AV node reentry tachycardia,atriventricular reentry tachycardia, WPW syndrome(Wolff-Parkinson-White), Mahaim tachycardia, hidden accessory conductionpathway, permanent junctional reentry tachycardia, focal atrialtachycardia, junctional ectopic tachycardia, atrial reentry tachycardia,ventricular tachycardia, ventricular flutter, ventricular fibrillation,sudden cardiac death.

In the context of the present invention, the term coronary heart diseasealso encompasses more specific or related types of disease, such as:ischaemic heart disease, stable angina pectoris, acute coronarysyndrome, unstable angina pectoris, NSTEMI (non-ST elevation myocardialinfarction), STEMI (ST elevation myocardial infarction), ischaemic heartmuscle damage, heart rhythm dysfunctions and myocardial infarction.

The compounds according to the invention are further suitable for theprophylaxis and/or treatment of polycystic kidney disease (PCKD) and ofthe syndrome of inappropriate ADH secretion (SIADH).

The compounds according to the invention are also suitable for treatmentand/or prophylaxis of renal disorders, in particular of acute andchronic renal insufficiency and acute and chronic renal failure.

In the context of the present invention, the term “acute renalinsufficiency” encompasses acute manifestations of kidney disease, ofkidney failure and/or renal insufficiency with and without the need fordialysis, and also underlying or related renal disorders such as renalhypoperfusion, intradialytic hypotension, volume deficiency (e.g.dehydration, blood loss), shock, acute glomerulonephritis,haemolytic-uraemic syndrome (HUS), vascular catastrophe (arterial orvenous thrombosis or embolism), cholesterol embolism, acute Bence-Joneskidney in the event of plasmacytoma, acute supravesicular orsubvesicular efflux obstructions, immunological renal disorders such askidney transplant rejection, immune complex-induced renal disorders,tubular dilatation, hyperphosphataemia and/or acute renal disorderscharacterized by the need for dialysis, including in the case of partialresections of the kidney, dehydration through forced diuresis,uncontrolled blood pressure rise with malignant hypertension, urinarytract obstruction and infection and amyloidosis, and systemic disorderswith glomerular factors, such as rheumatological-immunological systemicdisorders, for example lupus erythematodes, renal artery thrombosis,renal vein thrombosis, analgesic nephropathy and renal tubular acidosis,and X-ray contrast agent- and medicament-induced acute interstitialrenal disorders.

In the context of the present invention, the term “chronic renalinsufficiency” encompasses chronic manifestations of kidney disease, ofkidney failure and/or renal insufficiency with and without the need fordialysis, and also underlying or related renal disorders such as renalhypoperfusion, intradialytic hypotension, obstructive uropathy,glomerulopathy, glomerular and tubular proteinuria, renal oedema,haematuria, primary, secondary and chronic glomerulonephritis,membranous and membranoproliferative glomerulonephritis, Alportsyndrome, glomerulosclerosis, tubulointerstitial disorders, nephropathicdisorders such as primary and congenital kidney disease, renalinflammation, immunological renal disorders such as kidney transplantrejection, immune complex-induced renal disorders, diabetic andnon-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis,hypertensive nephrosclerosis and nephrotic syndrome, which can becharacterized diagnostically, for example, by abnormally reducedcreatinine and/or water excretion, abnormally elevated bloodconcentrations of urea, nitrogen, potassium and/or creatinine, alteredactivity of renal enzymes, for example glutamyl synthetase, alteredurine osmolarity or urine volume, elevated microalbuminuria,macroalbuminuria, glomerular and arteriolar lesions, tubular dilatation,hyperphosphataemia and/or the need for dialysis, and in the event ofrenal cell carcinoma, after partial resections of the kidney,dehydration through forced diuresis, uncontrolled blood pressure risewith malignant hypertension, urinary tract obstruction and infection andamyloidosis, and systemic disorders with glomerular factors, such asrheumatological-immunological systemic disorders, for example lupuserythematodes, and also renal artery stenosis, renal artery thrombosis,renal vein thrombosis, analgesic nephropathy and renal tubular acidosis.In addition, X-ray contrast agent- and medicament-induced chronicinterstitial renal disorders, metabolic syndrome and dyslipidaemia. Thepresent invention also encompasses the use of the compounds according tothe invention for treatment and/or prophylaxis of sequelae of renalinsufficiency, for example pulmonary oedema, heart failure, uraemia,anaemia, electrolyte disorders (for example hyperkalaemia,hyponatraemia) and disorders in bone and carbohydrate metabolism.

In addition, the compounds according to the invention are also suitablefor treatment and/or prophylaxis of pulmonary arterial hypertension(PAH) and other forms of pulmonary hypertension (PH), of chronicobstructive pulmonary disease (COPD), of acute respiratory distresssyndrome (ARDS), of acute lung injury (ALI), of alpha-1-antitrypsindeficiency (AATD), of pulmonary fibrosis, of pulmonary emphysema (forexample pulmonary emphysema caused by cigarette smoke), of cysticfibrosis (CF), of acute coronary syndrome (ACS), heart muscleinflammations (myocarditis) and other autoimmune cardiac disorders(pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathies),cardiogenic shock, aneurysms, sepsis (SIRS), multiple organ failure(MODS, MOF), inflammatory disorders of the kidney, chronic intestinaldisorders (IBD, Crohn's Disease, UC), pancreatitis, peritonitis,rheumatoid disorders, inflammatory skin disorders and inflammatory eyedisorders.

The compounds according to the invention can also be used for treatmentand/or prophylaxis of asthmatic disorders of varying severity withintermittent or persistent characteristics (refractive asthma, bronchialasthma, allergic asthma, intrinsic asthma, extrinsic asthma, medicament-or dust-induced asthma), of various forms of bronchitis (chronicbronchitis, infectious bronchitis, eosinophilic bronchitis), ofBronchiolitis obliterans, bronchiectasis, pneumonia, idiopathicinterstitial pneumonia, farmer's lung and related diseases, of coughsand colds (chronic inflammatory cough, iatrogenic cough), inflammationof the nasal mucosa (including medicament-related rhinitis, vasomotoricrhinitis and seasonal allergic rhinitis, for example hay fever) and ofpolyps.

The compounds described in the present invention are also activeingredients for control of central nervous system disorderscharacterized by disturbances of the NO/cGMP system. In particular, theyare suitable for improving perception, concentration, learning or memoryafter cognitive impairments like those occurring in particular inassociation with situations/diseases/syndromes such as mild cognitiveimpairment, age-associated learning and memory impairments,age-associated memory losses, vascular dementia, craniocerebral trauma,stroke, dementia occurring after strokes (post-stroke dementia),post-traumatic craniocerebral trauma, general concentration impairments,concentration impairments in children with learning and memory problems,Alzheimer's disease, Lewy body dementia, dementia with degeneration ofthe frontal lobes including Pick's syndrome, Parkinson's disease,progressive nuclear palsy, dementia with corticobasal degeneration,amyolateral sclerosis (ALS), Huntington's disease, demyelinization,multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia,HIV dementia, schizophrenia with dementia or Korsakoff's psychosis. Theyare also suitable for treatment and/or prevention of central nervoussystem disorders such as states of anxiety, tension and depression,CNS-related sexual dysfunctions and sleep disturbances, and forcontrolling pathological disturbances of the intake of food, stimulantsand addictive substances.

Because of their profile of biochemical and pharmacological properties,the compounds according to the invention are also especially suitablefor treatment and/or prevention of heart failure, coronary heartdisease, atrial and ventricular arrhythmia, kidney failure andnephropathy.

The compounds according to the invention can also be used for treatmentand/or prophylaxis of primary and secondary Raynaud's phenomenon,microcirculation impairments, claudication, peripheral and autonomicneuropathies, diabetic microangiopathies, diabetic retinopathy, diabeticulcers on the extremities, gangrene, CREST syndrome, erythematosis,onychomycosis, rheumatic disorders and for promoting wound healing.

The compounds according to the invention are additionally suitable fortreatment and/or prevention of ophthalmologic disorders, for exampleglaucoma, age-related macular degeneration (AMD), of dry (non-exudative)AMD, wet (exudative, neovascular) AMD, choroidal neovascularization(CNV), diabetic retinopathy, atrophic changes to the retinal pigmentepithelium (RPE), hypertrophic changes to the retinal pigmentepithelium, macular oedema, diabetic macular oedema, retinal veinocclusion, choroidal retinal vein occlusion, macular oedema due toretinal vein occlusion, angiogenesis at the front of the eye, forexample corneal angiogenesis, for example following keratitis, corneatransplant or keratoplasty, corneal angiogenesis due to hypoxia (as aresult of extensive wearing of contact lenses), pterygium conjunctiva,subretinal oedema and intraretinal oedema. In addition, the compoundsaccording to the invention are suitable for treatment and/or preventionof elevated and high intraocular pressure as a result of traumatichyphaema, periorbital oedema, postoperative viscoelastic retention orintraocular inflammation.

Moreover, the compounds according to the invention are suitable fortreatment and/or prophylaxis of hepatitis, neoplasms, osteoporosis,glaucoma and gastroparesis.

In addition, the compounds according to the invention are also suitablefor controlling cerebral blood flow and are thus effective agents forcontrolling migraines. They are also suitable for the prophylaxis andcontrol of sequelae of cerebral infarction (cerebral apoplexy) such asstroke, cerebral ischaemia and craniocerebral trauma. The compoundsaccording to the invention can likewise be used for controlling statesof pain and tinnitus.

The aforementioned well-characterized diseases in humans can also occurwith comparable aetiology in other mammals and can likewise be treatedtherein with the compounds of the present invention.

In the context of the present invention, the term “treatment” or“treating” includes inhibition, retardation, checking, alleviating,attenuating, restricting, reducing, suppressing, repelling or healing ofa disease, a condition, a disorder, an injury or a health problem, orthe development, the course or the progression of such states and/or thesymptoms of such states. The term “therapy” is understood here to besynonymous with the term “treatment”.

The terms “prevention”, “prophylaxis” and “preclusion” are usedsynonymously in the context of the present invention and refer to theavoidance or reduction of the risk of contracting, experiencing,suffering from or having a disease, a condition, a disorder, an injuryor a health problem, or a development or advancement of such statesand/or the symptoms of such states.

The treatment or prevention of a disease, a condition, a disorder, aninjury or a health problem may be partial or complete.

The present invention thus further provides for the use of the compoundsaccording to the invention for treatment and/or prevention of disorders,especially of the aforementioned disorders.

The present invention further provides for the use of the compoundsaccording to the invention for producing a medicament for the treatmentand/or prevention of disorders, especially of the aforementioneddisorders.

The present invention further provides a medicament comprising at leastone of the compounds of the invention for treatment and/or prevention ofdisorders, especially of the aforementioned disorders.

The present invention further provides for the use of the compoundsaccording to the invention in a method for treatment and/or preventionof disorders, especially of the aforementioned disorders.

The present invention further provides a method of treatment and/orprevention of disorders, especially of the aforementioned disorders,using an effective amount of at least one of the compounds according tothe invention.

The present invention further provides the compounds according to theinvention for use in a method of treatment and/or prevention ofdisorders, especially of the aforementioned disorders.

The compounds according to the invention can be used alone or, ifrequired, in combination with one or more other pharmacologically activesubstances, provided that this combination does not lead to undesirableand unacceptable side effects. The present invention therefore furtherprovides medicaments comprising at least one of the compounds accordingto the invention and one or more further active ingredients, especiallyfor treatment and/or prevention of the aforementioned disorders.Preferred examples of combination active ingredients suitable for thispurpose include:

-   -   active hypotensive ingredients, by way of example and with        preference from the group of calcium antagonists, angiotensin        AII antagonists, ACE inhibitors, NEP inhibitors, vasopeptidase        inhibitors, endothelin antagonists, renin inhibitors,        alpha-receptor blockers, beta-receptor blockers,        mineralocorticoid receptor antagonists, and rho kinase        inhibitors and the diuretics;    -   active antiarrhythmic ingredients, by way of example and with        preference sodium channel blockers, beta receptor blockers,        potassium channel blockers, calcium antagonists, If channel        blockers, digitalis, parasympatholytics (vagolytics),        sympathomimetics and other antiarrhythmics such as adenosine,        adenosine receptor agonists and vernakalant.    -   vasopressin receptor antagonists, by way of example and with        preference conivaptan, tolvaptan, lixivaptan, mozavaptan,        satavaptan, SR-121463, RWJ 676070 or BAY 86-8050;    -   compounds which affect the energy metabolism of the heart, by        way of example and with preference etomoxir, dichloroacetate,        ranolazine or trimetazidine;    -   compounds which inhibit the degradation of cyclic guanosine        monophosphate (cGMP) and/or cyclic adenosine monophosphate        (cAMP), for example inhibitors of phosphodiesterases (PDE) 1, 2,        3, 4 and/or 5, especially PDE 5 inhibitors such as sildenafil,        vardenafil and tadalafil;    -   antithrombotic agents, by way of example and with preference        from the group of the platelet aggregation inhibitors, the        anticoagulants or the profibrinolytic substances;    -   bronchodilatory agents, by way of example and with preference        from the group of the beta-adrenergic receptor agonists, such as        especially albuterol, isoproterenol, metaproterenol, terbutalin,        formoterol or salmeterol, or from the group of the        anticholinergics, such as especially ipratropium bromide;    -   anti-inflammatory agents, by way of example and with preference        from the group of the glucocorticoids, such as especially        prednisone, prednisolone, methylprednisolone, triamcinolone,        dexamethasone, beclomethasone, betamethasone, flunisolide,        budesonide or fluticasone;    -   active ingredients which modulate lipid metabolism, by way of        example and with preference from the group of the thyroid        receptor agonists, cholesterol synthesis inhibitors such as, by        way of example and preferably, HMG-CoA reductase inhibitors or        squalene synthesis inhibitors, the ACAT inhibitors, CETP        inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and/or PPAR-6        agonists, cholesterol absorption inhibitors, lipase inhibitors,        polymeric bile acid adsorbents, bile acid reabsorption        inhibitors and lipoprotein(a) antagonists.    -   compounds which inhibit the signal transduction cascade, by way        of example and with preference from the group of the kinase        inhibitors, especially from the group of the tyrosine kinase        and/or serine/threonine kinase inhibitors;    -   compounds which inhibit the degradation and alteration of the        extracellular matrix, by way of example and with preference        inhibitors of the matrix metalloproteases (MMPs), especially        inhibitors of chymase, stromelysin, collagenases, gelatinases        and aggrecanases (in this context particularly of MMP-1, MMP-3,        MMP-8, MMP-9, MMP-10, MMP-11 and MMP-13) and of metalloelastase        (MMP-12);    -   compounds which block the binding of serotonin to its receptor,        by way of example and with preference antagonists of the        5-HT_(2b) receptor;    -   organic nitrates and NO donors, for example sodium        nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide        dinitrate, molsidomine or SIN-1, and inhaled NO;    -   NO-independent but haem-dependent stimulators of soluble        guanylate cyclase, such as especially the compounds described in        WO 00/06568, WO 00/06569, WO 02/42301 and WO 03/095451;    -   NO- and haem-independent activators of soluble guanylate        cyclase, such as especially the compounds described in WO        01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462        and WO 02/070510;    -   compounds which increase the synthesis of cGMP, for example sGC        modulators such as, by way of example and with preference,        riociguat, cinaciguat, vericiguat or BAY 1101042    -   prostacyclin analogues, by way of example and with preference        iloprost, beraprost, treprostinil or epoprostenol;    -   compounds which inhibit soluble epoxide hydrolase (sEH), for        example N,N′-dicyclohexylurea,        12-(3-adamantan-1-ylureido)dodecanoic acid or        1-adamantan-1-yl-3-{5-[2-(2-ethoxyethoxy)ethoxy]pentyl}urea;    -   active ingredients which modulate glucose metabolism, for        example insulins, sulphonylureas, acarbose, DPP4 inhibitors,        GLP-1 analogues or SGLT-1 inhibitors.

In a preferred embodiment of the invention, the compounds according tothe invention are used in combination with a kinase inhibitor, by way ofexample and with preference bortezomib, canertinib, erlotinib,gefitinib, imatinib, lapatinib, lestaurtinib, lonafarnib, pegaptinib,pelitinib, semaxanib, sorafenib, regorafenib, sunitinib, tandutinib,tipifarnib, vatalanib, fasudil, lonidamine, leflunomide, BMS-3354825 orY-27632.

In a preferred embodiment of the invention, the compounds according tothe invention are used in combination with a serotonin receptorantagonist, by way of example and with preference PRX-08066.

Antithrombotic agents are preferably understood to mean compounds fromthe group of the platelet aggregation inhibitors, the anticoagulants orthe profibrinolytic substances.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a plateletaggregation inhibitor, by way of example and with preference aspirin,clopidogrel, ticlopidine or dipyridamole.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a thrombin inhibitor,by way of example and with preference ximelagatran, melagatran,bivalirudin or clexane.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a GPIIb/IIIaantagonist, by way of example and with preference tirofiban orabciximab.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a factor Xainhibitor, by way of example and with preference rivaroxaban, DU-176b,fidexaban, razaxaban, fondaparinux, idraparinux, PMD-3112, YN-150,KFA-1982, EMD-503982, MCN17, mLN-1021, DX 9065a, DPC 906, JTV 803,SSR-126512 or SSR-128428.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with heparin or with a lowmolecular weight (LMW) heparin derivative.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a vitamin Kantagonist, by way of example and with preference coumarin.

Hypotensive agents are preferably understood to mean compounds from thegroup of calcium antagonists, angiotensin AII antagonists, ACEinhibitors, endothelin antagonists, renin inhibitors, alpha-receptorblockers, beta-receptor blockers, mineralocorticoid receptorantagonists, rho kinase inhibitors, and the diuretics.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a calcium antagonist,by way of example and with preference nifedipine, amlodipine, verapamilor diltiazem.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an alpha-1-receptorblocker, by way of example and with preference prazosin.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a beta-receptorblocker, by way of example and with preference propranolol, atenolol,timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol,metipranolol, nadolol, mepindolol, carazalol, sotalol, metoprolol,betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol,carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucindolol.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an angiotensin AIIantagonist, by way of example and with preference losartan, candesartan,valsartan, telmisartan or embursatan, irbesartan, olmesartan, eprosartanor azilsartan or a dual angiotensin AII antagonist/NEP inhibitor, forexample and with preference Entresto (LCZ696, valsartan/sacubitril).

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an ACE inhibitor, byway of example and with preference enalapril, captopril, lisinopril,ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an endothelinantagonist, by way of example and with preference bosentan, darusentan,ambrisentan or sitaxsentan.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a renin inhibitor, byway of example and with preference aliskiren, SPP-600 or SPP-800.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a mineralocorticoidreceptor antagonist, by way of example and with preferencespironolactone or eplerenone, finerenone.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a rho kinaseinhibitor, by way of example and with preference fasudil, Y-27632,SLx2119, BF-66851, BF-66852, BF-66853, KI-23095, SB-772077, GSK-269962Aor BA-1049.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a diuretic, by way ofexample and with preference furosemide.

Lipid metabolism modifiers are preferably understood to mean compoundsfrom the group of the CETP inhibitors, thyroid receptor agonists,cholesterol synthesis inhibitors such as HMG-CoA reductase inhibitors orsqualene synthesis inhibitors, the ACAT inhibitors, MTP inhibitors,PPAR-alpha, PPAR-gamma and/or PPAR-6 agonists, cholesterol absorptioninhibitors, polymeric bile acid adsorbents, bile acid reabsorptioninhibitors, lipase inhibitors and the lipoprotein(a) antagonists.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a CETP inhibitor, byway of example and with preference torcetrapib (CP-529 414), JJT-705 orCETP vaccine (Avant).

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a thyroid receptoragonist, by way of example and with preference D-thyroxine,3,5,3′-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an HMG-CoA reductaseinhibitor from the class of statins, by way of example and withpreference lovastatin, simvastatin, pravastatin, fluvastatin,atorvastatin, rosuvastatin or pitavastatin.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a squalene synthesisinhibitor, by way of example and with preference BMS-188494 or TAK-475.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an ACAT inhibitor, byway of example and with preference avasimibe, melinamide, pactimibe,eflucimibe or SMP-797.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an MTP inhibitor, byway of example and with preference implitapide, BMS-201038, R103757 orJTT-130.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a PPAR-gamma agonist,by way of example and with preference pioglitazone or rosiglitazone.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a PPAR-6 agonist, byway of example and with preference GW 501516 or BAY 68-5042.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a cholesterolabsorption inhibitor, by way of example and with preference ezetimibe,tiqueside or pamaqueside.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a lipase inhibitor,by way of example and with preference orlistat.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a polymeric bile acidadsorber, by way of example and with preference cholestyramine,colestipol, colesolvam, CholestaGel or colestimide.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a bile acidreabsorption inhibitor, by way of example and with preference ASBT(=IBAT) inhibitors, for example AZD-7806, S-8921, AK-105, BARI-1741,SC-435 or SC-635.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a lipoprotein(a)antagonist, by way of example and with preference gemcabene calcium(CI-1027) or nicotinic acid.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with sGC modulators, byway of example and with preference riociguat, cinaciguat, vericiguat orBAY 1101042.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an active ingredientwhich modulates glucose metabolism, by way of example and withpreference insulin, a sulphonylurea, acarbose, DPP4 inhibitors, GLP-1analogues or SGLT-1 inhibitor.

Particular preference is given to combinations of the compoundsaccording to the invention with one or more further active ingredientsselected from the group consisting of active hypotensive ingredients,active antiarrhythmic ingredients, vasopressin receptor antagonists, PDE5 inhibitors, platelet aggregation inhibitors, sGC activators and sGCstimulators.

The present invention further provides medicaments which comprise atleast one compound according to the invention, typically together withone or more inert, nontoxic, pharmaceutically suitable excipients, andfor the use thereof for the aforementioned purposes.

The compounds according to the invention can act systemically and/orlocally. For this purpose, they can be administered in a suitablemanner, for example by the oral, parenteral, pulmonal, nasal,sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctivalor otic route, or as an implant or stent.

The compounds according to the invention can be administered inadministration forms suitable for these administration routes.

Suitable administration forms for oral administration are those whichwork according to the prior art and release the compounds according tothe invention rapidly and/or in a modified manner and which contain thecompounds according to the invention in crystalline and/or amorphizedand/or dissolved form, for example tablets (uncoated or coated tablets,for example with gastric juice-resistant or retarded-dissolution orinsoluble coatings which control the release of the compound accordingto the invention), tablets or films/oblates which disintegrate rapidlyin the oral cavity, films/lyophilizates, capsules (for example hard orsoft gelatin capsules), sugar-coated tablets, granules, pellets,powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can bypass an absorption step (e.g. take placeintravenously, intraarterially, intracardially, intraspinally orintralumbally) or include an absorption (e.g. take place inhalatively,intramuscularly, subcutaneously, intracutaneously, percutaneously orintraperitoneally). Administration forms suitable for parenteraladministration include preparations for injection and infusion in theform of solutions, suspensions, emulsions, lyophilizates or sterilepowders.

For the other administration routes, suitable examples are inhalablemedicament forms (including powder inhalers, nebulizers, meteredaerosols), nasal drops, solutions or sprays, tablets, films/oblates orcapsules for lingual, sublingual or buccal administration,suppositories, ear or eye preparations, vaginal capsules, aqueoussuspensions (lotions, shaking mixtures), lipophilic suspensions,ointments, creams, transdermal therapeutic systems (e.g. patches), milk,pastes, foams, sprinkling powders, implants or stents.

Oral and parenteral administration are preferred, especially oral,intravenous and intrapulmonary (inhalative) administration.

The compounds according to the invention can be converted to theadministration forms mentioned. This can be accomplished in a mannerknown per se by mixing with inert non-toxic pharmaceutically suitableauxiliaries. These auxiliaries include carriers (for examplemicrocrystalline cellulose, lactose, mannitol), solvents (e.g. liquidpolyethylene glycols), emulsifiers and dispersing or wetting agents (forexample sodium dodecylsulphate, polyoxysorbitan oleate), binders (forexample polyvinylpyrrolidone), synthetic and natural polymers (forexample albumin), stabilizers (e.g. antioxidants, for example ascorbicacid), colorants (e.g. inorganic pigments, for example iron oxides) andflavour and/or odour correctants.

In general, it has been found to be advantageous in the case ofparenteral administration to administer amounts of about 0.001 to 1mg/kg, preferably about 0.01 to 0.5 mg/kg, of body weight to achieveeffective results. In the case of oral administration the dosage isabout 0.01 to 100 mg/kg, preferably about 0.01 to 20 mg/kg and mostpreferably 0.1 to 10 mg/kg of body weight.

It may nevertheless be necessary in some cases to deviate from thestated amounts, specifically as a function of body weight, route ofadministration, individual response to the drug, nature of thepreparation and time or interval over which administration takes place.Thus, in some cases less than the abovementioned minimum amount may besufficient, while in other cases the upper limit mentioned must beexceeded. In the case of administration of greater amounts, it may beadvisable to divide them into several individual doses over the day.

The working examples which follow illustrate the invention. Theinvention is not restricted to the examples.

A. EXAMPLES Abbreviations and Acronyms

-   GP General Procedure-   abs. absolute-   aq. aqueous, aqueous solution-   br. broad (in NMR signal)-   Ex. Example-   Bu butyl-   c concentration-   approx. circa, about-   cat. catalytic-   CI chemical ionization (in MS)-   d doublet (in NMR)-   d day(s)-   DAST N,N-diethylaminosulphur trifluoride-   DCI direct chemical ionization (in MS)-   DCM dichloromethane-   dd doublet of doublets (in NMR)-   de diastereomeric excess-   dist. distilled-   DIPEA N,N-diisopropylethylamine-   DMAP 4-N,N-dimethylaminopyridine-   DMF N,N-dimethylformamide-   DMSO dimethyl sulphoxide-   dt doublet of triplets (in NMR)-   of th. of theory (in chemical yield)-   ee enantiomeric excess-   EI electron impact ionization (in MS)-   ent enantiomerically pure, enantiomer-   eq. equivalent(s)-   ESI electrospray ionization (in MS)-   Et ethyl-   GC gas chromatography-   GC/MS gas chromatography-coupled mass spectrometry-   h hour(s)-   HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HPLC high-pressure, high-performance liquid chromatography-   conc. concentrated (in the case of a solution)-   LC liquid chromatography-   LC/MS liquid chromatography-coupled mass spectrometry-   Lit. literature (reference)-   m multiplet (in NMR)-   M molar (in solution)-   Me methyl-   min minute(s)-   MS mass spectrometry-   NMP N-methyl-2-pyrrolidone-   NMR nuclear magnetic resonance spectrometry-   OXONE® potassium peroxomonosulphate (2 KHSO₅*KHSO₄*K₂SO₄)-   PyBOP 1-H-benzotriazol-1-yloxytris(pyrrolidino)phosphonium    hexafluorophosphate-   q (or quart) quartet (in NMR)-   qd quartet of doublets (in NMR)-   quant. quantitative (in chemical yield)-   quint quintet (in NMR)-   rac racemic, racemate-   RP reverse phase (in HPLC)-   RT room temperature-   R_(t) retention time (in HPLC, LC/MS)-   s singlet (in NMR)-   sept septet (in NMR)-   SFC supercritical liquid chromatography-   t triplet (in NMR)-   tBu tert-butyl-   td triplet of doublets (in NMR)-   THF tetrahydrofuran-   UV ultraviolet spectrometry-   cf. see-   v/v volume to volume ratio (of a solution)-   Xantphos 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene-   tog. together

HPLC and LC-MS Methods:

Method 1 (LC/MS):

Instrument: Waters Acquity SQD UPLC System; column: Waters Acquity UPLCHSS T3 1.8 μm 50×1 mm; eluent A: 1 l water+0.25 ml 99% formic acid,eluent B: 1 l acetonitrile+0.25 ml 99% formic acid; gradient: 0.0 min90% A→1.2 min 5% A→2.0 min 5% A; oven: 50° C.; flow rate: 0.40 ml/min;UV detection: 210-400 nm.

Method 2 (LC/MS):

MS instrument: Waters (Micromass) QM; HPLC instrument: Agilent 1100series; column: Agilent ZORBAX Extend-C18 3.0×50 mm 3.5 μm; eluent A: 1l water+0.01 mol ammonium carbonate, eluent B: 1 l acetonitrile;gradient: 0.0 min 98% A→0.2 min 98% A→3.0 min 5% A→4.5 min 5% A; oven:40° C.; flow rate: 1.75 ml/min; UV detection: 210 nm

Method 3 (LC/MS):

MS instrument type Thermo Scientific FT-MS; UHPLC+ instrument typeThermo Scientific UltiMate 3000; column Waters, HSST3, 2.1×75 mm, C181.8 μm; eluent A 1 l of water+0.01% formic acid; eluent B 1 l ofacetonitrile+0.01% formic acid; gradient 0.0 min 10% B→2.5 min 95% B→3.5min 95% B; oven 50° C.; flow rate 0.90 ml/min; UV detection 210nm/optimum integration path 210-300 nm

Method 4 (LC/MS):

Instrument: Waters ACQUITY SQD UPLC System; column: Waters Acquity UPLCHSS T3 1.8 μm 50×1 mm; eluent A: 1 l water+0.25 ml 99% formic acid,eluent B: 1 l acetonitrile+0.25 ml 99% formic acid; gradient: 0.0 min95% A→6.0 min 5% A→7.5 min 5% A; oven: 50° C.; flow rate: 0.35 ml/min;UV detection: 210-400 nm.

Method 5 (LC/MS):

Instrument: Agilent MS Quad 6150; HPLC: Agilent 1290; column: WatersAcquity UPLC HSS T3 1.8μ 50×2.1 mm; eluent A: 1 l water+0.25 ml 99%formic acid, eluent B: 1 l acetonitrile+0.25 ml 99% formic acid;gradient: 0.0 min 90% A→0.3 min 90% A→1.7 min 5% A→3.0 min 5% A; oven:50° C.; flow rate: 1.20 ml/min; UV detection: 205-305 nm.

Method 6 (GC-MS):

Instrument: Thermo DFS, Trace GC Ultra; column: Restek RTX-35, 15 m×200μm×0.33 μm; constant flow rate of helium: 1.20 ml/min; oven: 60° C.;inlet: 220° C.; gradient: 60° C., 30° C./min→300° C. (hold for 3.33min).

Method 7 (Preparative HPLC):

Column: Chromatorex C18, 250×30 mm; eluent A: water+0.1% formic acid,eluent B: acetonitrile; sample injection at 3.0 min, gradient: 0.0 min10% B→5.0 min 10% B→25 min 80% B→30 min 95% B→35 min 10% B; flow rate:50 ml/min, UV detection: 210 nm.

Further Details:

The percentages in the example and test descriptions which follow are,unless indicated otherwise, percentages by weight; parts are parts byweight. Solvent ratios, dilution ratios and concentration data for theliquid/liquid solutions are based in each case on volume.

In the case of purifications of compounds according to the invention bypreparative HPLC by the above-described methods in which the eluentscontain additives, for example trifluoroacetic acid, formic acid orammonia, the compounds according to the invention can be obtained insalt form, for example as trifluoroacetate, formate or ammonium salt, ifthe compounds according to the invention contain a sufficiently basic oracidic functionality. Such a salt can be converted to the correspondingfree base or acid by various methods known to the person skilled in theart.

Purity figures are generally based on corresponding peak integrations inthe LC/MS chromatogram, but may additionally also have been determinedwith the aid of the ¹H NMR spectrum. If no purity is indicated, thepurity is generally 100% according to automated peak integration in theLC/MS chromatogram, or the purity has not been determined explicitly.

Stated yields in % of theory are generally corrected for purity if apurity of <100% is indicated. In solvent-containing or contaminatedbatches, the formal yield may be “>100%”; in these cases the yield isnot corrected for solvent or purity.

The descriptions of the coupling patterns of ¹H NMR signals that followhave in some cases been taken directly from the suggestions of the ACDSpecManager (ACD/Labs Release 12.00, Product version 12.5) and have notnecessarily been strictly scrutinized. In some cases, the suggestions ofthe SpecManager were adjusted manually. Manually adjusted or assigneddescriptions are generally based on the optical appearance of thesignals in question and do not necessarily correspond to a strict,physically correct interpretation. In general, the stated chemical shiftrefers to the centre of the signal in question. In the case of broadmultiplets, an interval is given. Signals obscured by solvent or waterwere either tentatively assigned or have not been listed. Significantlybroadened signals—caused, for example, by rapid rotation of molecularmoieties or because of exchanging protons—were likewise assignedtentatively (often referred to as a broad multiple or broad singlet) orare not listed.

The ¹H NMR data of selected examples are stated in the form of ¹H NMRpeak lists. For each signal peak, first the δ value in ppm and then thesignal intensity in round brackets are listed. The δ value/signalintensity number pairs for different signal peaks are listed withseparation from one another by commas. The peak list for an exampletherefore takes the following form: δ₁ (intensity₁), δ₂ (intensity₂), .. . , δ_(i) (intensity_(i)), . . . δ_(n) (intensity_(n)).

The intensity of sharp signals correlates with the height of the signalsin a printed example of an NMR spectrum in cm and shows the true ratiosof the signal intensities in comparison with other signals. In the caseof broad signals, several peaks or the middle of the signal and therelative intensity thereof may be shown in comparison to the mostintense signal in the spectrum. The lists of the ¹H NMR peaks aresimilar to the conventional ¹H-NMR printouts and thus usually containall peaks listed in a conventional NMR interpretation. In addition, likeconventional ¹H NMR printouts, they may show solvent signals, signals ofstereoisomers of the target compounds which likewise form part of thesubject-matter of the invention, and/or peaks of impurities. The peaksof stereoisomers of the target compounds and/or peaks of impuritiesusually have a lower intensity on average than the peaks of the targetcompounds (for example with a purity of >90%). Such stereoisomers and/orimpurities may be typical of the particular preparation process. Theirpeaks can thus help in identifying reproduction of our preparationprocess with reference to “by-product fingerprints”. An expertcalculating the peaks of the target compounds by known methods (MestreC,ACD simulation, or using empirically evaluated expected values) can, ifrequired, isolate the peaks of the target compounds, optionally usingadditional intensity filters. This isolation would be similar to thepeak picking in question in conventional ¹H NMR interpretation. Adetailed description of the presentation of NMR data in the form of peaklists can be found in the publication “Citation of NMR Peaklist Datawithin Patent Applications” (cf. Research Disclosure Database Number605005, 2014, 1 Aug. 2014 orhttp://www.researchdisclosure.com/searching-disclosures). In the peakpicking routine described in Research Disclosure Database Number 605005,the parameter “MinimumHeight” can be set between 1% and 4%. Depending onthe type of chemical structure and/or depending on the concentration ofthe compound to be analysed, it may be advisable to set the parameters“MinimumHeight” of values <1%.

Melting points and melting-point ranges, if stated, are uncorrected.

All reactants or reagents whose preparation is not described explicitlyhereinafter were purchased commercially from generally accessiblesources. For all other reactants or reagents whose preparation likewiseis not described hereinafter and which were not commercially obtainableor were obtained from sources which are not generally accessible, areference is given to the published literature in which theirpreparation is described.

General Procedures

GP1

To a solution of the corresponding carboxylic acid (1-2 eq.) in DMF(0.08-0.12M) were added N,N-diisopropylethylamine (1.4-1.5 eq., or2.4-3.0 eq. when the amine was used in hydrochloride form) and HATU(1.0-1.65 eq.), and the mixture was stirred at RT for 30 min.Subsequently, the appropriate amine (1.04-1.5 eq.) was added and themixture was stirred at room temperature for a further 0.25-2 h. Thereaction was then ended by the addition of water and 1 M aqueoushydrochloric acid. The precipitate was filtered off, taken up in DCM,dried over magnesium sulphate and filtered, and the solvent was removedunder reduced pressure. Alternatively, the acidification was followed byextraction with ethyl acetate, drying of the combined organic phasesover magnesium sulphate, filtration and removal of the solvent underreduced pressure. The crude product was then purified either by normalphase chromatography (eluent: cyclohexane/ethyl acetate mixtures ordichloromethane/methanol mixtures) or preparative RP-HPLC(water/acetonitrile gradient).

GP2

Potassium carbonate or caesium carbonate (1.5-2.5 eq.) was baked in areaction vessel under reduced pressure. It was cooled to RT and floodedwith argon. Palladium acetate (0.1-0.36 eq.),9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (Xantphos, 0.18-0.36eq.) and dioxane (0.04-0.12M) were added, and the suspension wasdegassed in an argon stream at room temperature for 10 min.Subsequently, the appropriate amide (1.0-1.2 eq.) and the appropriate7-chloro-4-oxo-1,4-dihydro-1,8-naphthyridine (1.0 eq.) were added. Themixture was stirred at 80-110° C. for 1 h (or until conversion wascomplete by analytical HPLC or thin-layer chromatography withappropriate eluent mixtures). The mixture was cooled to RT and allvolatile components were removed under reduced pressure, oralternatively the reaction mixture was poured into water, the pH wasadjusted to pH 1 with 1M aqueous hydrochloric acid, the mixture wasextracted with ethyl acetate, the combined organic phases were washedwith saturated aqueous sodium chloride solution, dried over magnesiumsulphate and filtered, and the solvent was removed under reducedpressure. The crude product was then purified either by normal phasechromatography (eluent: cyclohexane/ethyl acetate mixtures ordichloromethane/methanol mixtures) or preparative RP-HPLC(water/acetonitrile gradient).

GP3

To a solution of the appropriate7-chloro-4-oxo-1,4-dihydro-1,8-naphthyridine in DMF (0.10-0.22 M) weresuccessively added the appropriate amine (1.2 eq.) and DIPEA (1.5-3.5eq.). The reaction solution was stirred at RT overnight. The crudeproduct was then purified either by normal phase chromatography (eluent:cyclohexane/ethyl acetate mixtures or dichloromethane/methanol mixtures)or preparative RP-HPLC (water/acetonitrile gradient).

Starting Compounds and Intermediates Example 1A rac-Methyl5-methyl-1,2-oxazolidine-5-carboxylate

To a solution of 20.0 g (288 mmol) of hydroxylamine hydrochloride an11.5 g (288 mmol) of sodium hydroxide in 20 ml of methanol and 40 ml ofwater were added dropwise 21.7 ml (290 mmol) of paraformaldehyde (37% inwater), at a sufficiently slow rate that the temperature did not exceed35° C. Subsequently, 31.0 ml (288 mmol) of methyl methacrylate wereadded and, on completion of addition, the mixture was stirred at 70° C.for 2 h. The mixture was cooled down to room temperature and extractedwith DCM. The combined organic phases were dried over sodium sulphateand filtered, and the solvent was removed under reduced pressure. 3.70 g(8.5% of theory, 96% purity) of the title compound were obtained aftervacuum distillation (0.7 mbar, 78-84° C.).

¹H-NMR (400 MHz, CDCl₃): δ [ppm]=6.05 (br. s, 1H), 3.76 (s, 3H),3.27-3.36 (m, 1H), 3.12-3.24 (m, 1H), 2.45-2.57 (m, 1H), 2.07-2.17 (m,1H), 1.55 (s, 3H).

GC/MS [Method 6]: R_(t)=3.51 min; MS: m/z=115.

Example 2A rac-3-Hydroxy-3-methylpyrrolidin-2-one

To a solution of 3.70 g (25.5 mmol) of the compound from Example 1A in300 ml of ethanol were added 3.80 g (3.57 mmol) of palladium (10% oncharcoal), and the mixture was stirred under a hydrogen atmosphere(standard pressure) overnight. The mixture was then filtered throughCelite and the solvent was removed under reduced pressure. The solidobtained was then stirred with acetonitrile, and the precipitate wasfiltered off with suction, washed twice with 1 ml of acetonitrile anddried under high vacuum. 1.97 g (55% of theory; 82% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, CDCl₃): δ [ppm]=5.71 (br. s, 1H), 3.37-3.43 (m, 1H),3.24-3.31 (m, 1H), 2.64 (s, 1H), 2.24-2.33 (m, 1H), 2.13-2.21 (m, 1H),1.40 (s, 3H).

GC/MS [Method 6]: R_(t)=3.14 min; MS: m/z=145.

Example 3A Ethyl7-chloro-1-(2-fluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate

To a solution of 11.1 g (35.0 mmol) of ethyl2-[(2,6-dichloropyridin-3-yl)carbonyl]-3-(dimethylamino)acrylate (CAS635309-52-3) in 80 ml of ethanol were added 4.67 g (42.0 mmol) of2-fluoroaniline in 21 ml of THF, and the mixture was stirred at RTovernight. Subsequently, the solvent was removed under reduced pressure,the residue was taken up in 110 ml of DMF, and 7.26 g (52.5 mmol) ofpotassium carbonate were added. The suspension was then stirred at 100°C. for 3 h, then cooled to RT and added to 200 ml of water. Theprecipitate was filtered off with suction, washed with water, thendissolved in 300 ml of ethyl acetate, washed three times with 50 ml ofwater, dried over sodium sulphate and filtered, and the solvent wasremoved under reduced pressure. The residue was taken up in a little DCMand purified by means of flash chromatography (ethyl acetate-cyclohexanegradient, then methanol-DCM, 5/95). 1.53 g (12% of theory, 99% purity)of the title compound were obtained. In addition, 1.33 g (11% of theory,99% purity) of the title compound from Example 32A were obtained (foranalysis see Example 32A).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.71 (s, 1H), 8.62 (d, 1H), 7.73-7.78(m, 1H), 7.65-7.69 (m, 1H), 7.65 (d, 1H), 7.50-7.56 (m, 1H), 7.43-7.48(m, 1H), 4.24 (q, 2H), 1.27 (t, 3H).

LC-MS (Method 1): R_(t)=0.94 min; 347 [M+H]⁺.

Example 4A Ethyl7-chloro-1-(2-chlorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate

To a solution of 6.05 g (19.0 mmol) of ethyl2-[(2,6-dichloropyridin-3-yl)carbonyl]-3-ethoxyacrylate (CAS157373-27-8) and 3.39 g (26.6 mmol) of 2-chloroaniline in 30.2 ml DCMwere added 23.2 ml (133 mmol) of DIPEA, and the mixture was stirred atRT for 4 h. Subsequently, 2.63 g (19.0 mmol) of potassium carbonate wereadded and the mixture was heated under reflux overnight. The mixture wasdiluted with 200 ml of DCM and washed twice with 75 ml of 1 M aqueoushydrochloric acid. The organic phase was dried over sodium sulphate andfiltered, and the solvent was removed under reduced pressure. Thesuspension obtained was stirred with 40 ml of tert-butyl methyl ether,and the precipitate was filtered off with suction, washed with 10 ml often-butyl methyl ether and dried under high vacuum. 3.71 g (53% oftheory, 99% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.65 (s, 1H), 8.63 (d, 1H), 7.82-7.75(m, 2H), 7.59-7.68 (m, 3H), 4.24 (q, 2H), 1.27 (t, 3H).

LC-MS (Method 3): R_(t)=1.81 min; 363 [M+H]⁺.

Example 5A Ethyl7-chloro-1-(2-chloro-4-fluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate

A mixture of 5 g (13.4 mmol) of ethyl2-[(2,6-dichloropyridin-3-yl)carbonyl]-3-ethoxyacrylate (CAS157373-27-8), 10.36 g (80.2 mmol) of DIPEA and 2.92 g (20.1 mmol) of2-chloro-4-fluoroaniline in 50 ml of dichloromethane was stirred at 20°C. for 20 hours. Subsequently, the mixture was concentrated underreduced pressure, then taken up in ethyl acetate and washed three timeswith water and once with saturated sodium chloride solution. The organicphase was concentrated under reduced pressure and dried under highvacuum. The residue was then dissolved in 80 ml of dioxane, a solutionof 1 g (9.3 mmol) of potassium tert-butoxide in 20 ml of dioxane wasadded while cooling with ice, and the mixture was stirred at 23° C. for15 h. The solution was then added to ice-water, and the precipitatedsolid was filtered off with suction, washed with water and dried underhigh vacuum. 3.3 g (56% of theory, 87% purity) of the title compoundwere obtained.

LC-MS (Method 1): R_(t)=1.04 min; m/z=381.1 [M+H]⁺.

Example 6A Ethyl1-(2,4-difluorophenyl)-7-(dimethylamino)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate

A mixture of 2 g (5.5 mmol) of ethyl7-chloro-1-(2,4-difluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate(preparation described in DE 4301246, Example U, S.26), 894 mg (11 mmol)of dimethylamine hydrochloride and 2.48 g (19.2 mmol) of DIPEA in 50 mlof acetonitrile was stirred at 23° C. for 18 hours. Subsequently, themixture was concentrated under reduced pressure, water was added and theaqueous phase was extracted with ethyl acetate. The combined organicphases were washed with saturated sodium chloride solution, dried overmagnesium sulphate and concentrated under reduced pressure. This gave1.92 g (94% of theory) of the title compound.

LC-MS (Method 1): R_(t)=0.95 min; m/z=374.1 [M+H]⁺.

In analogy to Example 6A, the example compounds shown in Table 1A wereprepared by reacting ethyl7-chloro-1-(2,4-difluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylateor the compound from Example 5A with the appropriate amines (or saltsthereof) and DIPEA under the reaction conditions described. Differencesare specified in the respective examples.

TABLE 1A Ex. IUPAC name/structure/(yield) Analytical data 7A Ethyl1-(2,4-difluorophenyl)-7-(methylamino)-4- LC-MS (Method 1): R_(t) = 0.89min oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate MS (ESpos): m/z =360.2 [M + H]⁺

8A Ethyl 1-(2,4-difluorophenyl)-4-oxo-7-(propan-2- LC-MS (Method 1):R_(t) = 0.99 min ylamino)-1,4-dihydro-1,8-naphthyridine-3-carboxylate MS(ESpos): m/z = 388.3 [M + H]⁺

9A Ethyl 1-(2,4-difluorophenyl)-7-[(2-hydroxy- LC-MS (Method 1): R_(t) =0.85 min ethyl)(methyl)amino]-4-oxo-1,4-dihydro-1,8- MS (ESpos): m/z =404.2. [M + H]⁺ naphthyridine-3-carboxylate

10A Ethyl 1-(2,4-difluorophenyl)-7-[(2-hydroxy- LC-MS (Method 1): R_(t)= 0.80 min ethyl)amino]-4-oxo-1,4-dihydro-1,8-naphthyridine- MS (ESpos):m/z = 390.2 [M + H]⁺ 3-carboxylate

11A Ethyl 1-(2,4-difluorophenyl)-7-[(2-fluoro- LC-MS (Method 1): R_(t) =0.90 min ethyl)amino]-4-oxo-1,4-dihydro-1,8-naphthyridine- MS (ESpos):m/z = 392.1 [M + H]⁺ 3-carboxylate

12A Ethyl 1-(2,4-difluorophenyl)-7-[(2- LC-MS (Method 1): R_(t) = 0.96min fluoroethyl)(methyl)amino]-4-oxo-1,4-dihydro-1,8- MS (ESpos): m/z =406.1 [M + H]⁺ naphthyridine-3-carboxylate

13A Ethyl 1-(2,4-difluorophenyl)-7-(3,3- LC-MS (Method 1): R_(t) = 1.02min difluoropyrrolidin-1-yl)-4-oxo-1,4-dihydro-1,8- MS (ESpos): m/z =436.1 [M + H]⁺ naphthyridine-3-carboxylate

14A Ethyl 1-(2,4-difluorophenyl)-7-[(3R)-3- LC-MS (Method 1): R_(t) =0.97 min fluoropyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8- MS (ESpos): m/z =417.9 [M + H]⁺ naphthyridine-3-carboxylate

15A Ethyl 1-(2,4-difluorophenyl)-7-[(3S)-3- LC-MS (Method 1): R_(t) =0.97 min fluoropyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8- MS (ESpos): m/z =418.1 [M + H]⁺ naphthyridine-3-carboxylate

16A Ethyl 1-(2,4-difluorophenyl)-4-oxo-7-(3,3,4,4- LC-MS (Method 1):R_(t) = 1.05 min tetrafluoropyrrolidin-1-yl)-1,4-dihydro-1,8- MS(ESpos): m/z = 472.2 [M + H]⁺ naphthyridine-3-carboxylate

17A Ethyl 7-[(2,2-difluoroethyl)(methyl)amino]-1-(2,4- LC-MS (Method 1):R_(t) = 0.98 min difluorophenyl)-4-oxo-1,4-dihydro-1,8- MS (ESpos): m/z= 424.1 [M + H]⁺ naphthyridine-3-carboxylate

18A Ethyl 7-[(2,2-difluoroethyl)amino]-1-(2,4- LC-MS (Method 1): R_(t) =0.93 min difluorophenyl)-4-oxo-1,4-dihydro-1,8- MS (ESpos): m/z = 409.9[M + H]⁺ naphthyridine-3-carboxylate

19A Ethyl 1-(2,4-difluorophenyl)-4-oxo-7-(1,3- LC-MS (Method 2): R_(t) =1.01 min thiazolidin-3-yl)-1,4-dihydro-1,8-naphthyridine-3- MS (ESpos):m/z = 418.2 [M + H]⁺ carboxylate

20A rac-Ethyl 1-(2,4-difluorophenyl)-7-[2- LC-MS (Method 1): R_(t) =0.79 min (hydroxymethyl)morpholin-4-yl]-4-oxo-1,4- MS (ESpos): m/z =446.3 [M + H]⁺ dihydro-1,8-naphthyridine-3-carboxylate

21A rac-Ethyl 1-(2,4-difluorophenyl)-7-[2- LC-MS (Method 1): R_(t) =0.87 min (hydroxymethyl)pyrrolidin-1-yl]-4-oxo-1,4- MS (ESpos): m/z =430.2 [M + H]⁺ dihydro-1,8-naphthyridine-3-carboxylate

22A rac-Ethyl 1-(2,4-difluorophenyl)-7-[3- LC-MS (Method 1): R_(t) =0.81 min (hydroxymethyl)morpholin-4-yl]-4-oxo-1,4- MS (ESpos): m/z =446.2 [M + H]⁺ dihydro-1,8-naphthyridine-3-carboxylate

23A rac-Ethyl 1-(2,4-difluorophenyl)-7-(3-hydroxy-3- LC-MS (Method 1)R_(t) = 0.91 min methylpiperidin-1-yl)-4-oxo-1,4-dihydro-1,8- MS(ESpos): m/z = 444.3 [M + H]⁺ naphthyridine-3-carboxylate

24A Ethyl 1-(2,4-difluorophenyl)-7-[methyl(2,2,2- LC-MS (Method 1):R_(t) = 1.02 min trifluoroethyl)amino]-4-oxo-1,4-dihydro-1,8- MS(ESpos): m/z = 442.2 [M + H]⁺ naphthyridine-3-carboxylate

25A Ethyl 1-(2,4-difluorophenyl)-7-(morpholin-4-yl)-4- LC-MS (Method 1):R_(t) = 0.93 min oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate MS(ESpos): m/z = 416.2 [M + H]⁺

26A Ethyl 1-(2,4-difluorophenyl)-4-oxo-7-(pyrrolidin-1- LC-MS (Method1): R_(t) = 1.06 min yl)-1,4-dihydro-1,8-naphthyridine-3-carboxylate MS(ESpos): m/z = 400.2 [M + H]⁺

27A Ethyl 1-(2,4-difluorophenyl)-7-[4-hydroxy-4- LC-MS (Method 1): Rt =0.76 min (hydroxymethyl)piperidin-1-yl]-4-oxo-1,4-dihydro- MS (ESpos):m/z = 460.3 [M + H]+ 1,8-naphthyridine-3-carboxylate

28A Ethyl 1-(2-chloro-4-fluorophenyl)-7- LC-MS (Method 1): R_(t) = 1.01min (dimethylamino)-4-oxo-1,4-dihydro-1,8- MS (ESpos): m/z = 390.2 [M +H]⁺ naphthyridine-3-carboxylate

29A Ethyl 1-(2,4-difluorophenyl)-7-[4- LC-MS (Method 1): R_(t) = 0.91min (methoxycarbonyl)piperazin-1-yl]-4-oxo-1,4- MS (ESpos): m/z = 473.3[M + H]⁺ dihydro-1,8-naphthyridine-3-carboxylate

Example 30A Ethyl1-(2,4-difluorophenyl)-4-oxo-7-[(2,2,2-trifluoroethyl)amino]-1,4-dihydro-1,8-naphthyridine-3-carboxylate

A mixture of 1 g (2.7 mmol) of ethyl7-chloro-1-(2,4-difluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate(preparation described in DE 4301246, Example U, S.26) and 1.9 g (19mmol) of 2,2,2-trifluoroethylamine in 3.5 ml of acetonitrile was stirredin a microwave at 160° C. for one hour. Subsequently, the mixture wasbrought to pH 3 with 1 M aqueous hydrochloric acid, water was added, andthe precipitated solid was filtered off with suction, washed with waterand petroleum ether and dried under high vacuum. This gave 1.2 g (66% oftheory) of the title compound.

¹H-NMR (400 MHz, DMSO-d₆): [ppm]=2.40 (s, 3H), 7.49-7.56 (m, 3H),7.61-7.63 (m, 2H), 7.90-7.94 (m, 2H), 8.01 (d, 1H), 14.39 (br. s, 1H).

LC-MS (Method 1): R_(t)=0.91 min; MS (ESpos): m/z=428.1 [M+H]⁺

Example 31A Ethyl1-(2,4-difluorophenyl)-7-(1,1-dioxido-1,3-thiazolidin-3-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate

A mixture of 6.1 g (11.5 mmol; 79% purity) of the compound from Example19A, 28.3 g (46 mmol) of OXONE® and 8 g (46 mmol) of dipotassiumhydrogenphosphate in 88 ml of dioxane and 44 ml water was stirred at 23°C. for 8 hours and then left to stand for 13 h. Subsequently, 1 ml of 1M aqueous hydrochloric acid and 100 ml of water were added, and theprecipitated solid was filtered off with suction, washed with water andpetroleum ether and dried under high vacuum. This gave 3.72 g (58% oftheory) of the title compound.

LC-MS (Method 1): Rt=0.83 min; m/z=450.2 [M+H]⁺.

Example 32A Ethyl7-(dimethylamino)-1-(2-fluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate

As described in the preparation of the compound from Example 3A, 11.1 g(35.0 mmol) of ethyl2-[(2,6-dichloropyridin-3-yl)carbonyl]-3-(dimethylamino)acrylate wereused to obtain 1.33 g (11% of theory, 99% purity) of the title compound.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.43 (s, 1H), 8.21 (d, 1H), 7.70-7.65(m, 1H), 7.64-7.57 (m, 1H), 7.50-7.44 (m, 1H), 7.43-7.38 (m, 1H), 6.82(d, 1H), 4.20 (q, 2H), 2.90 (br. s, 6H), 1.25 (t, 3H).

LC-MS (Method 3): R_(t)=1.64 min; 356 [M+H]⁺.

Example 33A7-Chloro-1-(2-fluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid

To a suspension of 1.52 g (4.38 mmol) of the compound from Example 3A in21.7 ml of THF were added 8.8 ml of aqueous sodium hydroxide solution (1M, 8.8 mmol), and the reaction mixture was stirred at room temperaturefor 3 h. The mixture was then diluted with 100 ml of water and the pHwas adjusted to pH 1 with 1 M aqueous hydrochloric acid. The precipitatewas filtered off with suction, washed with water and dried in a vacuumdrying cabinet at 40° C. overnight. 1.22 g (86% of theory, 99% purity)of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=14.1 (br. s, 1H), 9.02 (s, 1H), 8.80(d, 1H), 7.81 (d, 1H), 7.79-7.74 (m, 1H), 7.72-7.66 (m, 1H), 7.58-7.52(m, 1H), 7.50-7.44 (m, 1H).

LC-MS (Method 3): R_(t)=1.66 min; 319 [M+H]⁺.

Example 33Brac-1-(2-Fluorophenyl)-7-(3-hydroxy-2-oxopyrrolidin-1-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid

According to GP2, 260 mg (816 μmol) of the compound from Example 33Awere reacted with 82.5 mg (816 μmol) of 3-hydroxypyrrolidin-2-one (CAS:15166-68-4) in the presence of 282 mg (2.04 mmol) of potassiumcarbonate, 33.0 mg (147 μmol) of palladium(II) acetate and 170 mg (294μmol) of Xantphos in 8.24 ml of 1,4-dioxane at 80° C. The reactionmixture was poured into 30 ml of water and adjusted to pH 1 with 1 Maqueous hydrochloric acid. The mixture was extracted withdichloromethane. The combined organic phases were dried over sodiumsulphate and filtered, and the solvent was removed under reducedpressure. The crude product was purified in two runs by means ofpreparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm, solvent:acetonitrile/0.05% formic acid gradient; (0 to 3 min. 10% acetonitrileto 35 min. 90% acetonitrile and a further 3 min. 90% acetonitrile), and161.5 mg (50% of theory, 97.6% purity) of the title compound wereobtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=14.63 (s, 1H), 8.99 (s, 1H), 8.78 (d,1H), 8.58 (dd, 1H), 7.81-7.73 (m, 1H), 7.72-7.65 (m, 1H), 7.58-7.50 (m,1H), 7.49-7.42 (m, 1H), 5.92 (d, 1H), 4.46-4.32 (min, 1H), 3.60-3.45 (m,1H), 3.34-3.20 (m, 1H, partially under the water signal), 2.34-2.24 (m,1H), 1.84-1.66 (m, 1H).

LC-MS (Method 3): R_(t)=1.28 min; 384 [M+H]⁺.

Example 34A7-Chloro-1-(2-chlorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid

To a suspension of 3.70 g (10.2 mmol) of the compound from Example 4A in50.5 ml of THF were added 20.4 ml of aqueous sodium hydroxide solution(1 M, 20.4 mmol), and the reaction mixture was stirred at roomtemperature for 3 h. The mixture was then diluted with 100 ml of waterand the pH was adjusted to pH 1 with 1N aqueous hydrochloric acid. Theprecipitate was filtered off with suction, washed with water and driedin a vacuum drying cabinet at 40° C. overnight. 3.18 g (92% of theory,99% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=14.1 (br. s, 1H), 8.92 (s, 1H), 8.79(d, 1H), 7.83-7.74 (m, 3H), 7.70-7.59 (m, 2H).

LC-MS (Method 3): R_(t)=1.79 min; 335 [M+H]⁺.

Example 35A7-Chloro-1-(2,4-difluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid

To 3 g (8.2 mmol) of ethyl7-chloro-1-(2,4-difluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate(preparation described in DE 4301246, Example U, S.26) in 60 ml of THFwere added 16.5 ml (16.4 mmol) of 1 M aqueous lithium hydroxidesolution, and the mixture was stirred at 23° C. for 2 h. The mixture wasdiluted with 120 ml of water and then a pH of 1 was established withconc. hydrochloric acid. The precipitated solid was filtered off withsuction, washed with water and dried under high vacuum. This gave 2.62 g(95% of theory) of the title compound.

LC-MS (Method 1): R_(t)=0.93 min; m/z=337.1 [M+H]⁺.

Example 36A1-(2,4-Difluorophenyl)-7-(dimethylamino)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid

Method A:

A solution of 1.9 g (5.1 mmol) of the compound from Example 6A in 24 mlof 18 percent aqueous hydrochloric acid was stirred at 100° C. for 9 h.Subsequently, the mixture was filtered, and the filtercake was washedwith 0.5 M aqueous hydrochloric acid and ethanol and dried under highvacuum. This gave 1.58 g (89% of theory) of the title compound.

Method B:

To 4.39 g (11.8 mmol) of the compound from Example 6A in 276 ml of THFwere added 47 ml (47 mmol) of 1 M aqueous lithium hydroxide solution,and the mixture was stirred at 23° C. for 16 h. After 2.5 days, a pH of3 was established by adding 1 M aqueous hydrochloric acid. Afteraddition of water, the precipitated solid was filtered off with suction,washed with water and diethyl ether and dried under high vacuum. Thisgave 4 g (99% of theory) of the title compound.

LC-MS (Method 1): R_(t)=0.97 min; m/z=346.2 [M+H]⁺.

In analogy to Example 36A, the example compounds shown in Table 2A wereprepared by reacting the corresponding ester compounds from Examples7A-31A with 18 percent aqueous hydrochloric acid or aqueous 1 to 2 Mlithium hydroxide solution under the reaction conditions described. Thereaction time was between 2 h and 16 h. Differences are specified in therespective examples.

TABLE 2A Ex. IUPAC name/structure/(yield) Analytical data 37A1-(2,4-Difluorophenyl)-7-(methylamino)-4-oxo- LC-MS (Method 1): R_(t) =0.84 min 1,4-dihydro-1,8-naphthyridine-3-carboxylic acid MS (ESpos): m/z= 332.1 [M + H]⁺

38A 1-(2,4-Difluorophenyl)-4-oxo-7-(propan-2-yla- LC-MS (Method 1):R_(t) = 0.98 min mino)-1,4-dihydro-1,8-naphthyridine-3-carboxylic MS(ESpos): m/z = 360.2 [M + H]⁺ acid

39A 1-(2,4-Difluorophenyl)-7-[(2-hydroxyethyl)(meth- LC-MS (Method 1):R_(t) = 0.80 min yl)amino]-4-oxo-1,4-dihydro-1,8-naphthyridine- MS(ESpos): m/z = 376.1 [M + H]⁺ 3-carboxylic acid

40A 1-(2,4-Difluorophenyl)-7-[(2-hydroxy- LC-MS (Method 1): R_(t) = 1.34min ethyl)amino]-4-oxo-1,4-dihydro-1,8- MS (ESpos): m/z = 362.0 [M + H]⁺naphthyridine-3-carboxylic acid

41A 1-(2,4-Difluorophenyl)-7-[(2-fluoroethyl)amino]- LC-MS (Method 1):R_(t) = 0.87 min 4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic MS(ESpos): m/z = 364.0 [M + H]⁺ acid

42A 1-(2,4-Difluorophenyl)-7-[(2- LC-MS (Method 1): R_(t) = 0.87 minfluoroethyl)(methyl)amino]-4-oxo-1,4-dihydro- MS (ESpos): m/z = 378.1[M + H]⁺ 1,8-naphthyridine-3-carboxylic acid

43A 1-(2,4-Difluorophenyl)-7-(3,3-difluoropyrrolidin- LC-MS (Method 1):R_(t) = 1.01 min 1-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3- MS(ESpos): m/z = 408.1 [M + H]⁺ carboxylic acid

44A 1-(2,4-Difluorophenyl)-7-[(3R)-3-fluoropyrrolidin- LC-MS (Method 1):R_(t) = 0.95 min 1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3- MS(ESpos): m/z = 390.1 [M + H]⁺ carboxylic acid

45A 1-(2,4-Difluorophenyl)-7-[(3S)-3-fluoropyrrolidin- LC-MS (Method 1):R_(t) = 0.95 min 1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3- MS(ESpos): m/z = 390.2 [M + H]⁺ carboxylic acid

46A 1-(2,4-Difluorophenyl)-4-oxo-7-(3,3,4,4-tetra- LC-MS (Method 1):R_(t) = 1.05 min fluoropyrrolidin-1-yl)-1,4-dihydro-1,8-naphthyridine-MS (ESpos): m/z = 444.0 [M + H]⁺ 3-carboxylic acid

47A 1-(2,4-Difluorophenyl)-4-oxo-7-[(2,2,2-trifluoro- LC-MS (Method 1):R_(t) = 0.88 min ethyl)amino]-1,4-dihydro-1,8-naphthyridine-3- MS(ESpos): m/z = 400.1 [M + H]⁺ carboxylic acid

48A 7-[(2,2-Difluoroethyl)(methyl)amino]-1-(2,4- LC-MS (Method 1): R_(t)= 0.96 min difluorophenyl)-4-oxo-1,4-dihydro-1,8- MS (ESpos): m/z =396.2 [M + H]⁺ naphthyridine-3-carboxylic acid

49A 7-[(2,2-Difluoroethyl)amino]-1-(2,4-difluoro- LC-MS (Method 1):R_(t) = 0.88 min phenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3- MS(ESpos): m/z = 382.2 [M + H]⁺ carboxylic acid

50A 1-(2,4-Difluorophenyl)-7-(1,1-dioxido-1,3-thiazolidin- LC-MS (Method1): R_(t) = 0.70 min 3-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3- MS(ESpos): m/z = 422.2 [M + H]⁺ carboxylic acid

51A rac-1-(2,4-Difluorophenyl)-7-[2-(hydroxymeth- LC-MS (Method 1):R_(t) = 0.70 min yl)morpholin-4-yl]-4-oxo-1,4-dihydro-1,8- MS (ESpos):m/z = 418.1 [M + H]⁺ naphthyridine-3-carboxylic acid

52A rac-1-(2,4-Difluorophenyl)-7-[2-(hydroxymeth- LC-MS (Method 1):R_(t) = 0.85 min thyl)pyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8- MS(ESpos): m/z = 40.2 [M + H]⁺ naphthyridine-3-carboxylic acid

53A rac-1-(2,4-Difluorophenyl)-7-[3-(hydroxymeth- LC-MS (Method 1):R_(t) = 0.76 min yl)morpholin-4-yl]-4-oxo-1,4-dihydro-1,8- MS (ESpos):m/z = 418.2 [M + H]⁺ naphthyridine-3-carboxylic acid

54A rac-1-(2,4-Difluorophenyl)-7-(3-hydroxy-3- LC-MS (Method 1): R_(t) =0.90 min methylpiperidin-1-yl)-4-oxo-1,4-dihydro-1,8- MS (ESpos): m/z =416.1 [M + H]⁺ naphthyridine-3-carboxylic acid

55A 1-(2,4-Difluorophenyl)-7-[methyl(2,2,2-trifluoro- LC-MS (Method 1):R_(t) = 1.00 min ethyl)amino]-4-oxo-1,4-dihydro-1,8- MS (ESpos): m/z =414.2 [M + H]⁺ naphthyridine-3-carboxylic acid

56A 1-(2,4-Difluorophenyl)-7-(morpholin-4-yl)-4-oxo- LC-MS (Method 1):R_(t) = 0.90 min 1,4-dihydro-1,8-naphthyridine-3-carboxylic acid MS(ESpos): m/z = 388.2 [M + H]⁺

57A 1-(2,4-Difluorophenyl)-4-oxo-7-(pyrrolidin-1-yl)- LC-MS (Method 1):R_(t) = 1.05 min 1,4-dihydro-1,8-naphthyridine-3-carboxylic acid MS(ESpos): m/z = 372.2 [M + H]⁺

58A 1-(2,4-Difluorophenyl)-7-[4-hydroxy-4-(hydroxy-methyl)piperidin-1-yl]-4-oxo-1,4-dihydro- 1,8-naphthyridine-3-carboxylicacid

59A 1-(2,4-Difluorophenyl)-4-oxo-7-(1,3-thiazolidin-3- LC-MS (Method 3):R_(t) = 1.84 min yl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic MS(ESpos): m/z = 390.0 [M + H]⁺ acid

60A 1-(2-Chloro-4-fluorophenyl)-7-(dimethylamino)-4- LC-MS (Method 1):R_(t) = 2.16 min oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic MS(ESpos): m/z = 362.1 [M + H]⁺ acid

Example 61A1-(2,4-Difluorophenyl)-4-oxo-7-(2-oxo-1,3-oxazolidin-3-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid

A mixture of 300 mg (0.67 mmol) of ethyl7-chloro-1-(2,4-difluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate(preparation described in DE 4301246, Example U, S.26), 232 mg (2.7mmol) of 2-oxazolidinone, 184 mg (1.3 mmol) of potassium carbonate, 129mg (0.68 mmol) of copper(I) iodide and 51 mg (0.69 mmol) oftrans-N,N′-dimethyl-1,2-cyclohexanediamine in 7.5 ml of DMF was stirredat 110° C. for 3 h and then at 23° C. for a further 13 h. Subsequently,127 mg (0.67 mmol) of copper(I) iodide and 40 mg (0.66 mmol) oftrans-N,N′-dimethyl-1,2-cyclohexanediamine were added and the mixturewas stirred at 130° C. for a further 10 h, the mixture was filtered andthe filtrate was concentrated by preparative HPLC (eluent:acetonitrile/water gradient with 0.1% formic acid). This gave 28 mg (6%of theory, 59% purity (HPLC)) of the target compound, which was used forthe next stage without further purification.

LC-MS (Method 1): Rt=2.38 min; m/z=388.0 [M+H]⁺.

Example 62A7-(Dimethylamino)-1-(2-fluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid

To a suspension of 1.33 g (3.74 mmol) of the compound from Example 32Ain 18.5 ml of THF were added 7.5 ml of aqueous sodium hydroxide solution(1 M, 7.5 mmol), and the reaction mixture was stirred at roomtemperature for 3 h. The mixture was then diluted with 100 ml of waterand the pH was adjusted to pH 1 with 1 M aqueous hydrochloric acid. Theprecipitate was filtered off with suction, washed with water and driedin a vacuum drying cabinet at 40° C. overnight. 1.13 g (91% of theory,99% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=15.4 (br. s, 1H), 8.73 (s, 1H), 8.32(d, 1H), 7.75-7.70 (m, 1H), 7.67-7.61 (m, 1H), 7.53-7.46 (m, 1H),7.45-7.40 (m, 1H), 7.02 (d, 1H), 2.95 (br. s, 6H).

LC-MS (Method 3): R_(t)=1.62 min; 328 [M+H]⁺.

Example 63A1-(2,4-Difluorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl)]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid

According to GP2, 2.50 g (7.43 mmol) of the compound from Example 35Awere reacted with 750 mg (7.43 mmol) of (4S)-4-hydroxypyrrolidin-2-onein the presence of 4.84 g (14.9 mmol) of caesium carbonate, 300 mg (1.34mmol) of palladium(II) acetate and 773 mg (1.34 mmol) of Xantphos in 75ml of dioxane at 80° C.

The reaction mixture was cooled to room temperature and poured into 300ml of water. The pH was adjusted to 1 with 1N aqueous hydrochloric acidand the precipitate was filtered off with suction, washed with n-hexaneand dried under high vacuum. The crude product was purified by means offlash chromatography (dichloromethane/methanol gradient), and 292 mg(6.4% of theory; 65% purity) of the title compound were obtained.

LC-MS (Method 1): R_(t)=0.73 min; 402 [M+H]⁺.

Example 64A1-(2-Chlorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl)]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid

According to GP2, 500 mg (1.49 mmol) of the compound from Example 34Awere reacted with 150 mg (1.49 mmol) of (4S)-4-hydroxypyrrolidin-2-onein the presence of 515 mg (3.73 mmol) of potassium carbonate, 60.3 mg(269 μmol) of palladium(II) acetate and 311 mg (537 μmol) of Xantphos in15 ml of dioxane at 90° C. The crude product was purified by flashchromatography (dichloromethane/methanol gradient) and preparative HPLC(column: Kromasil C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient (0 to 3 min 10% acetonitrile, to 35 min 90%acetonitrile and for a further 3 min 90% acetonitrile). 67.4 mg (11% oftheory, 99% purity) of the title compound were obtained (as anatropisomer mixture).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=14.66 (br. s, 1H), 8.92 (s, 1H), 8.76(d, 1H), 8.57 (dd, 1H), 7.82-7.75 (m, 2H), 7.70-7.59 (m, 2H), 5.32 (dd,1H), 4.27-4.20 (m, 1H), 3.60-3.52 (m, 1H), 3.40-3.33 (m, 1H), 2.99-2.88(m, 1H), 2.40-2.32 (m, 1H).

LC-MS (Method 3): R_(t)=1.30/1.36 min; 400 [M+H]⁺.

Example 65A7-Chloro-1-(2,4-difluorophenyl)-4-oxo-N-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

To 90 mg (0.27 mmol) of the compound from Example 35A and 68 mg (0.67mmol) of N-methylmorpholine in 3.3 ml of DMF was added, at 0° C., 0.54ml (0.54 mmol) of isopropyl chloroformate (1 M in toluene), and themixture was then stirred at 0° C. for 1 h. Then, at 0° C., 53 mg (0.35mmol) of 1-adamantanamine were added and the mixture was stirred at 20°C. for 2 h. The mixture was purified via preparative HPLC (eluent:acetonitrile/water gradient with 0.1% formic acid). This gave 48 mg (36%of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.46 min; m/z=470.2 [M+H]⁺.

In analogy to Example 65A, the example compounds shown in Table 3A wereprepared by reacting the compound from Example 35A with the appropriateamines (or salts thereof) under the reaction conditions described.Differences are specified in the respective examples.

Illustrative Workup of the Reaction Mixture:

The reaction mixture was then added to water and adjusted to pH 1 with 1M aqueous hydrochloric acid. The solvent (toluene) was removed underreduced pressure and the precipitate formed was filtered off and driedunder reduced pressure. The purification was effected, by way ofexample, by column chromatography (silica gel,cyclohexane→cyclohexane/ethyl acetate 10:1) or preparative thin-layerchromatography (silica gel, DCM).

TABLE 3A Ex. IUPAC name/structure/(yield) Analytical data 66Arac-7-Chloro-1-(2,4-difluorophenyl)-4-oxo-N- LC-MS (Method 1): R_(t) =1.21 min (1,1,1-trifluorobutan-2-yl)-1,4-dihydro-1,8- MS (ESpos): m/z =446.2 [M + H]⁺ naphthyridine-3-carboxamide

Solvent: NMP (62% of theory) 67A7-Chloro-1-(2,4-difluorophenyl)-4-oxo-N-[(2R)- LC-MS (Method 1): R_(t) =1.16 min 1,1,1-trifluorobutan-2-yl)-1,4-dihydro-1,8- MS (ESpos): m/z =446.1 [M + H]⁺ naphthyridine-3-carboxamide

Workup: The mixture was added to water and adjusted to pH 1 with aqueous1 M hydrochloric acid. Then the toluene was removed under reducedpressure, and the precipitate was filtered off, dried under high vacuumand purified by silica gel chromatography (cyclohexane →cyclohexane/ethyl acetate 10:1). (59% of theory) 68A7-Chloro-1-(2,4-difluorophenyl)-4-oxo-N-[(2R)- LC-MS (Method 1): R_(t) =1.20 min 1,1,1-trifluorobutan-2-yl)-1,4-dihydro-1,8-naph- MS (ESpos):m/z = 446.2 [M + H]⁺ thyridine-3-carboxamide

Workup: The mixture was added to water and adjusted to pH 1 with aqueous1 M hydrochlorid acid. Then the toluene was removed under reducedpressure, and the precipitate was filtered off, dried under high vacuumand purified by silica gel chromatography (cyclohexane →cyclohexane/ethyl acetate 10:1). (70% of theory) 69Arac-7-Chloro-1-(2,4-difluorophenyl)-4-oxo-N- LC-MS (Method 1): R_(t) =1.16 min (1,1,1-trifluoropropan-2-yl)-1,4-dihydro-1,8-naph- MS (ESpos):m/z = 432.0 [M + H]⁺ thyridine-3-carboxamide

(76% of theory) 70A 7-Chloro-1-(2,4-difluorophenyl)-N-(4-methylbicycloLC-MS (Method 1): R_(t) = 1.39 min[2.2.2]oct-1-yl)-4-oxo-1,4-dihydro-1,8- MS (ESpos): m/z = 458.3 [M + H]⁺naphthyridine-3-carboxamide

Purification by preparative thin-layer chromatography (silica gel, DCM)(23% of theory) 71A7-Chloro-1-(2,4-difluorophenyl)-N-[2-(2,6-difluorophenyl) LC-MS (Method1): R_(t) = 1.26 min propan-2-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-MS (ESpos): m/z = 490.3 [M + H]⁺ 3-carboxamide

Purification via preparative thin-layer chromatography (silica gel, DCM)(22% of theory) 72A7-Chloro-N-(2,6-dichlorobenzyl)-1-(2,4-difluorophenyl)- LC-MS (Method1): R_(t) = 1.24 min 4-oxo-1,4-dihydro-1,8-naphthyridine-3- MS (ESpos):m/z = 494.1 [M + H]⁺ carboxamide

(88% of theory)

Example 73Arac-7-Chloro-N-[1-(2-chlorophenyl)-2,2,2-trifluoroethyl]-1-(2,4-difluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 1.50 g (4.46 mmol) of the compound from Example 35Awere reacted with 1.40 mg (6.68 mmol) ofrac-1-(2-chlorophenyl)-2,2,2-trifluoroethanamine in the presence of 1.69g (4.46 mmol) of HATU and 1.09 ml (6.24 mmol) ofN,N-diisopropylethylamine in 45 ml of dimethylformamide. The crudeproduct was purified by means of flash chromatography (cyclohexane/ethylacetate gradient), and 1.73 g (71% of theory; 96% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.05 (d, 1H), 8.92 (s, 1H), 8.79 (d,1H), 7.91-7.75 (m, 1H), 7.77 (d, 1H), 7.68-7.48 (m, 5H), 7.41-7.33 (m,1H), 6.53-6.42 (m, 1H).

LC-MS (Method 1): R_(t)=1.30 min; 528 [M+H]⁺.

Example 74Arac-7-Chloro-1-(2,4-difluorophenyl)-4-oxo-N-[1-(trifluoromethoxy)propan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 2.50 g (7.43 mmol) of the compound from Example 35Awere reacted with 1.28 mg (6.68 mmol) ofrac-1-(trifluoromethoxy)propan-2-amine in the presence of 3.11 g (8.17mmol) of HATU and 1.29 ml (7.43 mmol) of N,N-diisopropylethylamine in 90ml of dimethylformamide. After monitoring the reaction overnight, afurther 1.55 g (4.08 mmol) of HATU and 647 μl (3.71 mmol) ofN,N-diisopropylethylamine were added and the mixture was stirred at roomtemperature overnight. The crude product was purified by means of flashchromatography (cyclohexane/ethyl acetate gradient), and 2.38 g (69% oftheory; 99% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=9.72 (d, 1H), 8.83 (s, 1H), 8.74 (d,1H), 7.90-7.82 (m, 1H), 7.73 (d, 1H), 7.67-7.60 (m, 1H), 7.41-7.34 (m,1H), 4.42-4.33 (m, 1H), 4.24-4.15 (m, 2H), 1.26 (d, 3H).

LC-MS (Method 3): R_(t)=2.18 min; 462 [M+H]⁺.

Example 75A7-Chloro-1-(2,4-difluorophenyl)-4-oxo-N-[1-phenyl-2-(trifluoromethoxy)ethyl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 1.1 g (3.3 mmol) of the compound from Example 35A werereacted with 1.22 g (4.90 mmol) of(−)-1-phenyl-2-(trifluoromethoxy)ethanamine hydrochloride (97% purity,optical rotation: −21.13° in methanol c=0.5300 g/100 ml, 589 nm, 20° C.)in the presence of 1.24 g (3.27 mmol) of HATU and 1.14 ml (6.53 mmol) ofN,N-diisopropylethylamine in 33 ml of dimethylformamide. The crudeproduct was purified by means of flash chromatography (cyclohexane/ethylacetate gradient), and 880 mg (49% of theory; 95% purity) of the titlecompound (non-racemic mixture) were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.37 (d, 1H), 8.84 (s, 1H), 8.78 (d,1H), 7.91-7.77 (m, 1H), 7.74 (d, 1H), 7.67-7.59 (m, 1H), 7.51-7.29 (m,6H), 5.56-5.48 (m, 1H), 4.55-4.41 (m, 2H).

LC-MS (Method 3): R_(t)=2.36 min; 524 [M+H]⁺.

Example 76Arac-7-Chloro-1-(2,4-difluorophenyl)-4-oxo-N-[1-(trifluoromethoxy)butan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Racemate)

According to GP1, 100 mg (285 μmol) of the compound from Example 35A(96% purity) were reacted with 82.8 g (428 μmol) ofrac-1-(trifluoromethoxy)butan-2-amine hydrochloride in the presence of108 mg (285 μmol) of HATU and 119 μl (684 μmol) ofN,N-diisopropylethylamine in 3 ml of dimethylformamide. The crudeproduct was purified by means of flash chromatography (cyclohexane/ethylacetate gradient), and 101 mg (75% of theory; 100% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=9.69 (d, 1H), 8.83 (s, 1H), 8.74 (d,1H), 7.90-7.83 (m, 1H), 7.73 (d, 1H), 7.67-7.60 (m, 1H), 7.41-7.34 (m,1H), 4.27-4.13 (m, 3H), 1.76-1.52 (m, 2H), 0.94 (t, 3H).

LC-MS (Method 1): R_(t)=1.25 min; 476 [M+H]⁺.

Example 77Arac-7-Chloro-1-(2,4-difluorophenyl)-N-[1-(2-fluorophenyl)ethyl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 100 mg (285 μmol) of the compound from Example 35A(96% purity) were reacted with 59.5 g (428 μmol) ofrac-1-(2-fluorophenyl)ethylamine in the presence of 108 mg (285 μmol) ofHATU and 70 μl (0.40 mmol) of N,N-diisopropylethylamine in 3 ml ofdimethylformamide. The crude product was purified by means of flashchromatography (cyclohexane/ethyl acetate gradient), and 97.3 mg (75% oftheory; 100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.12 (d, 1H), 8.79 (s, 1H), 8.75 (d,1H), 7.89-7.78 (m, 1H), 7.74 (d, 1H), 7.67-7.58 (m, 1H), 7.49-7.41 (m,1H), 7.40-7.29 (m, 2H), 7.24-7.17 (m, 2H), 5.44-5.34 (m, 1H), 1.52 (d,3H).

LC-MS (Method 1): R_(t)=1.23 min; 458 [M+H]⁺.

Example 78Arac-7-Chloro-1-(2,4-difluorophenyl)-4-oxo-N-(1,1,1-trifluoro-3-methoxy-2-methylpropan-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 100 mg (285 μmol) of the compound from Example 35A(96% purity) were reacted with 87.2 mg (428 μmol) ofrac-1,1,1-trifluoro-3-methoxy-2-methylpropan-2-amine hydrochloride inthe presence of 108 mg (285 μmol) of HATU and 119 μl (684 μmol) ofN,N-diisopropylethylamine in 3 ml of dimethylformamide. The crudeproduct was purified by means of flash chromatography (cyclohexane/ethylacetate gradient), and 112 mg (82% of theory; 100% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.28 (br. s, 1H), 8.84 (s, 1H), 8.75(d, 1H), 7.90-7.82 (m, 1H), 7.74 (d, 1H), 7.67-7.60 (m, 1H), 7.41-7.34(m, 1H), 3.90-3.84 (m, 1H), 3.77-3.67 (m, 1H), 3.36 (s, 3H), 1.64 (s,3H).

LC-MS (Method 1): R_(t)=1.20 min; 476 [M+H]⁺.

Example 79A7-Chloro-1-(2,4-difluorophenyl)-4-oxo-N-[4-(trifluoromethyl)tetrahydro-2H-pyran-4-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 100 mg (285 μmol) of the compound from Example 35A (9Mpurity) were reacted with 87.9 g (428 μmol) of4-(trifluoromethyl)tetrahydro-2H-pyran-4-amine hydrochloride in thepresence of 108 mg (285 μmol) of HATU and 119 μl (684 μmol) ofN,N-diisopropylethylamine in 3 ml of dimethylformamide. The crudeproduct was purified by means of flash chromatography (cyclohexane/ethylacetate gradient), and 108 mg (77% of theory; 100% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.08 (s, 1H), 8.87 (s, 1H), 8.76 (d,1H), 7.90-7.83 (m, 1H), 7.76 (d, 1H), 7.68-7.61 (m, 1H), 7.41-7.34 (m,1H), 3.95-3.85 (m, 2H), 3.57-3.45 (m, 2H), 2.47-2.39 (m, 1H), 1.95-1.83(m, 2H).

LC-MS (Method 1): R_(t)=1.17 min; 488 [M+H]⁺.

Example 80Arac-7-Chloro-1-(2,4-difluorophenyl)-N-[1-(2,6-difluorophenyl)-2,2,2-trifluoroethyl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 3.00 g (8.91 mmol) of the compound from Example 35Awere reacted with 1.96 g (9.27 mmol) ofrac-1-(2,6-difluorophenyl)-2,2,2-trifluoroethanamine in the presence of3.39 g (8.91 mmol) of HATU and 2.17 ml (12.5 mmol) ofN,N-diisopropylethylamine in 90 ml of dimethylformamide. The crudeproduct was purified by means of flash chromatography (cyclohexane/ethylacetate mixture, 5:1), and 2.10 g (44% of theory; 100% purity) of thetitle compound were obtained.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=11.14 (d, 1H), 8.93 (s, 1H), 8.79 (d,1H), 7.93-7.75 (m, 1H), 7.76 (d, 1H), 7.68-7.59 (m, 2H), 7.42-7.27 (m,3H), 6.50-6.38 (m, 1H).

LC-MS (Method 1): R_(t)=1.29 min; 530.1 [M+H]⁺.

Example 81A7-Chloro-N-(2,6-dichlorophenyl)-1-(2,4-difluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide

To a suspension of 1.00 g (2.97 mmol) of the compound from Example 35Ain 10 ml of THF were added 0.29 ml (3.3 mmol) of oxalyl chloride andcatalytic amounts of dimethylformamide. After the evolution of gas hadended, the reaction mixture was heated at 60° C. for 1 h and then cooleddown to RT. All the volatile components were removed under reducedpressure and the residue was taken up in 20 ml of DMF. In parallel, 481mg (2.97 mmol) of 2,6-dichloroaniline were dissolved in 10 ml of DMF,and 119 mg (2.97 mmol) of sodium hydride (60% in mineral oil) wereadded. The mixture was stirred at RT for 30 min. Subsequently, the abovesolution was added rapidly and the reaction mixture was stirred at RTovernight. The reaction was ended by adding water and ethyl acetate, andthe phases were separated. The organic phase was washed twice with waterand with saturated aqueous sodium chloride solution, dried overmagnesium sulphate and filtered, and the solvent was removed underreduced pressure. The crude product was taken up in a little DCM andpurified by means of flash chromatography (cyclohexane/ethyl acetategradient). 298 mg (18% of theory, 88% purity) of the title compound wereobtained.

LC-MS (Method 3): R_(t)=2.30 min; 480 [M+H]⁺.

Example 82A7-Chloro-1-(2-fluorophenyl)-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 250 mg (784 μmol) of the compound from Example 33Awere reacted with 192 mg (1.18 mmol) of (R)-1-trifluoromethylpropylaminehydrochloride in the presence of 298 mg (784 μmol) of HATU and 410 μl(2.35 mmol) of N,N-diisopropylethylamine in 8.1 ml of dimethylformamide.The crude product was purified by means of flash chromatography(cyclohexane/ethyl acetate gradient), and 139 mg (41% of theory; 99%purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.00 (d, 1H), 8.86 (s, 1H), 8.76 (d,1H), 7.83-7.65 (m, 3H), 7.58-7.51 (m, 1H), 7.50-7.44 (m, 1H), 4.85-4.69(m, 1H), 1.96-1.82 (m, 1H), 1.75-1.60 (m, 1H), 0.98 (t, 3H).

LC-MS (Method 1): R_(t)=1.17 min; 428 [M+H]⁺.

Example 83A tert-Butyl5-[8-(2,4-difluorophenyl)-5-oxo-6-{[(2R)-1,1,1-trifluorobutan-2-yl]carbamoyl}-5,8-dihydro-1,8-naphthyridin-2-yl]-1-oxohexahydropyrrol[3,4-c]pyrrole-2(1H)-carboxylate(Diastereomer Mixture)

According to GP3, 200 mg (449 μmol) of the compound from Example 67Awere reacted with 128 mg (538 μmol) of rac-tert-butyl1-oxooctahydropyrrolo[3,4-c]pyrrole-2-carboxylate in the presence of 117μl (673 μmol) of N,N-diisopropylethylamine in 4.4 ml ofdimethylformamide. The crude product was diluted with acetonitrile andpurified by means of preparative HPLC (column: Chromatorex C18, 10 μm,125×30 mm, solvent: acetonitrile/0.05% formic acid gradient; (0 to 3min. 10% acetonitrile to 35 min. 90% acetonitrile and a further 3 min.90% acetonitrile), and 224 mg (79% of theory, 100% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.47 (d, 1H), 8.62 (s, 1H), 8.32 (d,1H), 7.77-7.86 (m, 1H), 7.54-7.65 (m, 1H), 7.28-7.38 (m, 1H), 6.65-6.90(br. s, 1H), 4.68-4.80 (m, 1H), 2.97-3.90 (m, 8H), 1.82-1.94 (m, 1H),1.57-1.70 (m, 1H), 1.43 (s, 9H), 0.96 (t, 3H).

LC-MS (Method 3): R_(t)=2.20 min; 636 [M+H]⁺.

Example 84A Ethyl7-chloro-1-(2,6-difluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate

To a solution of 6.05 g (19.0 mmol) of ethyl2-[(2,6-dichloropyridin-3-yl)carbonyl]-3-ethoxyacrylate (CAS157373-27-8) and 3.44 g (26.6 mmol) of 2,6-difluoroaniline in 30.2 ml ofDCM were added 23.2 ml (133 mmol) of DIPEA, and the mixture was stirredat room temperature for 4 h. The mixture was diluted with 200 ml of DCMand washed twice with 75 ml of 1 M aqueous hydrochloric acid. Theorganic phase was dried over sodium sulphate and filtered, and thesolvent was removed under reduced pressure. The residue was stirred with40 ml of tert-butyl methyl ether and the precipitate was washed with 10ml of tert-butyl methyl ether. Subsequently, the precipitate was admixedwith 30 ml of DCM and 2.63 g (19.0 mmol) of potassium carbonate, and themixture was heated under reflux overnight. The mixture was cooled to RT,diluted with 200 ml of DCM and washed twice with 75 ml of 1 M aqueoushydrochloric acid. The organic phase was dried over magnesium sulphateand filtered, and the solvent was removed under reduced pressure. Theresidue was taken up in 100 ml of acetonitrile and 30 ml of DMF, andheated to 50° C. 1.66 g (12.0 mmol) of potassium carbonate were added at50° C. and the mixture was stirred for a further 1 h. The reactionmixture was cooled down to RT and poured into 200 ml of aqueous 1 Mhydrochloric acid. The mixture was extracted three times with 150 ml ofDCM. The combined organic phases were dried over magnesium sulphate andfiltered, and the solvent was removed under reduced pressure. Theresidue was stirred with 200 ml of water and the precipitate wasfiltered off with suction and dried under high vacuum. 4.19 g (60% oftheory, 100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=8.92 (s, 1H), 8.63 (d, 1H), 7.78-7.70(m, 1H), 7.68 (d, 1H), 7.49-7.43 (m, 2H), 4.25 (q, 2H), 1.28 (t, 3H).

LC-MS (Method 3): R_(t)=1.78 min; 365 [M+H]⁺.

Example 85A7-Chloro-1-(2,6-difluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid

To a suspension of 3.83 g (10.5 mmol) of the compound from Example 84Ain 31.5 ml of water were successively added 31.5 ml of concentratedhydrochloric acid and 31.5 ml of tetrahydrofuran. The resultingsuspension was stirred vigorously at 120° C. for 4 h and subsequentlycooled down to RT. The mixture was diluted with 100 ml of water, and theprecipitate was filtered off with suction and dried under high vacuum.3.39 g (95% of theory, 98.9% purity) of the title compound wereobtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.86 (s, 1H), 9.25 (s, 1H), 8.79 (d,1H), 7.82 (d, 1H), 7.80-7.72 (m, 1H), 7.51-7.43 (m, 2H).

LC-MS (Method 3): R_(t)=1.74 min; 337 [M+H]⁺.

Example 86A7-Chloro-1-(2,6-difluorophenyl)-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 500 mg (1.43 mmol) of the compound from Example 85Awere reacted with 350 mg (2.14 mmol) of (R)-1-trifluoromethylpropylaminehydrochloride in the presence of 542 mg (1.43 mmol) of HATU and 596 μl(3.42 mmol) of DIPEA in 14.3 ml of DMF. The crude product was purifiedby means of flash chromatography (cyclohexane/ethyl acetate gradient),and 493 mg (77% of theory; 99% purity) of the title compound wereobtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=9.89 (d, 1H), 9.09 (s, 1H), 8.76 (d,1H), 7.78 (d, 1H), 7.80-7.71 (m, 1H), 7.50-7.43 (m, 2H), 4.84-4.71 (m,1H), 1.96-1.84 (m, 1H), 1.75-1.61 (m, 1H), 0.98 (t, 3H).

LC-MS (Method 3): R_(t)=2.30 min; 446 [M+H]⁺.

Example 87A rac-Ethyl1-(2,4-difluorophenyl)-7-(3-hydroxypyrrolidin-1-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate

To a solution of 3.00 g (8.23 mmol) of ethyl7-chloro-1-(2,4-difluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate(preparation described in DE 4301246, Example U, S.26) in 20.8 ml of DMFwere successively added 1.33 ml (16.5 mmol) of rac-3-pyrrolidinol and5.01 ml (28.8 ml) of DIPEA. The mixture was stirred at RT overnight. Thereaction was ended by adding water and the precipitate was filtered offwith suction, washed with water and dried under high vacuum. 3.33 g(97.5% of theory, 100% purity) of the title compound were obtained.

LC-MS (Method 1): R_(t)=0.83 min; 416 [M+H]⁺.

Example 88Arac-1-(2,4-Difluorophenyl)-7-(3-hydroxypyrrolidin-1-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid

3.30 g (8.02 mmol) of the compound from Example 87A were partlydissolved and partly suspended in 25 ml of water, 25 ml of concentratedhydrochloric acid were added and the mixture was heated under reflux for6 h. The reaction mixture was left to stand at RT over the weekend. Theprecipitate was subsequently filtered off with suction, washed withaqueous 0.5 M hydrochloric acid and ethanol, and dried under highvacuum. 2.14 g (67% of theory, 97% purity) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=0.80 min; 388 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=8.77 (s, 1H), 8.33-8.27 (m, 1H),7.85-7.76 (m, 1H), 7.62-7.54 (m, 1H), 7.37-7.29 (m, 1H), 6.88-6.79 (m,1H), 4.43-3.01 (m, 6H, partially under the water peak), 2.07-1.73 (m,2H).

Example 89A Ethyl7-chloro-4-oxo-1-[2-(trifluoromethyl)phenyl]-1,4-dihydro-1,8-naphthyridine-3-carboxylate

To a solution of 6.05 g (19.0 mmol) of ethyl2-[(2,6-dichloropyridin-3-yl)carbonyl]-3-ethoxyacrylate (CAS157373-27-8) and 4.59 g (28.5 mmol) of 2-trifluoromethylaniline in 30 mlDCM were added 23.2 ml (133 mmol) of DIPEA, and the mixture was stirredat RT for 4 h. Subsequently, 2.63 g (19.0 mmol) of potassium carbonatewere added and the mixture was heated under reflux overnight. Themixture was diluted with 400 ml of DCM and washed twice with 150 ml of 1M aqueous hydrochloric acid. The organic phase was dried over sodiumsulphate and filtered, and the solvent was removed under reducedpressure. The suspension obtained was stirred with 40 ml of tert-butylmethyl ether, and the precipitate was filtered off with suction, washedwith 10 ml of tert-butyl methyl ether and dried under high vacuum. 4.21g (55% of theory, 99% purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.81 min; 397 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=8.71 (s, 1H), 8.62 (d, 1H), 8.04-8.00(m, 1H), 7.99-7.93 (m, 1H), 7.89-7.83 (m, 2H), 7.63 (d, 1H), 4.23 (q,2H), 1.26 (t, 3H).

Example 90A7-Chloro-4-oxo-1-[2-(trifluoromethyl)phenyl]-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid

To a suspension of 4.10 g (10.3 mmol) of the compound from Example 89Ain 51 ml of THF were added 20.7 ml of aqueous sodium hydroxide solution(20.7 mmol), and the reaction mixture was stirred at RT for 3 h. Themixture was then diluted with 250 ml of water and the pH was adjusted topH 1 with 1N aqueous hydrochloric acid. The precipitate was filtered offwith suction, washed with water and dried in a vacuum drying cabinet at40° C. overnight. 3.77 g (98% of theory, 99% purity) of the titlecompound were obtained.

LC-MS (Method 3): R_(t)=1.84 min; 369 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=14.03 (br. s, 1H), 9.08 (s, 1H), 8.80(d, 1H), 8.06-8.01 (m, 1H), 8.00-7.94 (m, 1H), 7.92-7.84 (m, 2H), 7.79(d, 1H).

Example 91A7-Chloro-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1-[2-(trifluoromethyl)phenyl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 250 mg (678 μmol) of the compound from Example 90Awere reacted with 166 mg (1.02 mmol) of (R)-1-trifluoromethylpropylaminehydrochloride in the presence of 258 mg (678 μmol) of HATU and 354 μl(2.03 mmol) of DIPEA in 7 ml of DMF. The crude product was purified bymeans of flash chromatography (25 g, silica cartridge, flow rate: 25ml/min, detection: 220 nm and 270 nm, cyclohexane/ethyl acetate gradient(0% ethyl acetate, then 20% ethyl acetate, then 30% ethyl acetate). Thetwo atropisomers were separated, and 56.6 mg (17% of theory, 99% purity,atropisomer 1, Example 92A) and 58.8 mg (18% of theory, 99% purity,atropisomer 2, Example 93A) of the title compound were obtained asatropisomers.

Example 92A7-Chloro-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1-[2-(trifluoromethyl)phenyl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Atropisomer 1)

LC-MS (Method 3): R_(t)=2.32 min; 478 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=9.99 (d, 1H), 8.86 (s, 1H), 8.75 (d,1H), 8.06-8.02 (m, 1H), 8.00-7.95 (m, 1H), 7.91-7.85 (m, 2H), 7.73 (d,1H), 4.83-4.70 (m, 1H), 1.96-1.84 (m, 1H), 1.76-1.62 (m, 1H), 0.99 (t,3H).

Example 93A7-Chloro-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1-[2-(trifluoromethyl)phenyl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Atropisomer 2)

LC-MS (Method 3): R_(t)=2.31 min; 478 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=9.99 (d, 1H), 8.87 (s, 1H), 8.76 (d,1H), 8.06-8.02 (m, 1H), 8.00-7.95 (m, 1H), 7.91-7.85 (m, 2H), 7.74 (d,1H), 4.83-4.70 (m, 1H), 1.96-1.83 (m, 1H), 1.74-1.61 (m, 1H), 0.96 (t,3H).

Example 94A (3R)-2,5-Dioxotetrahydrofuran-3-yl trifluoroacetate

At 0° C., 12.0 ml (85.0 mmol) of trifluoroacetic anhydride were added to5.70 g (42.5 mmol) of (2R)-2-hydroxysuccinic acid, and the mixture wasstirred at 0° C. for 1 h and at room temperature for 2 h. Subsequently,all volatile components were removed under reduced pressure at roomtemperature. The crude product was used in Example 95A without furtherpurification.

Example 95A (3R)-3-Hydroxy-4-methoxy-4-oxobutanoic acid

5.17 ml (128 mmol) of methanol were added to 9.02 g (42.5 mmol) of thecompound from Example 94A, and the mixture was stirred at roomtemperature for 4 h. Subsequently, excess methanol was removed underreduced pressure and the residue was recrystallized from diethylether/cyclohexane. The solid was dried under high vacuum. This gave 5.84g (92.8% of theory) of the title compound.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.31 (br. s, 1H), 5.68 (br. s, 1H),4.35 (dd, 1H), 3.63 (s, 3H), 2.63 (dd, 1H), 2.52-2.45 (m, 1H).

Example 96A Methyl (5S)-2-oxo-1,3-oxazolidine-5-carboxylate

To a solution of 5.84 g (39.4 mmol) of the compound from Example 95A in159 ml of tert-butanol were added 11.9 g (43.4 mmol) ofdiphenylphosphoryl azide and 6.05 ml (43.4 mmol) of triethylamine, andthen the mixture was heated under reflux for 4 h. The mixture was cooleddown to room temperature and the solvent was removed under reducedpressure. The residue was purified by means of flash chromatography(ethyl acetate/cyclohexane gradient). Finally, recrystallization waseffected from ethyl acetate/cyclohexane, the solid was dried under highvacuum and 3.29 g (57.7% of theory) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.79 (s, 1H), 5.15 (dd, 1H),3.80-3.74 (m, 1H), 3.73 (s, 3H), 3.52-3.46 (m, 1H).

Example 97A (3S)-2,5-Dioxotetrahydrofuran-3-yl trifluoroacetate

At 0° C., 12.0 ml (85.0 mmol) of trifluoroacetic anhydride were added to5.70 g (42.5 mmol) of (2S)-2-hydroxysuccinic acid, and the mixture wasstirred at 0° C. for 1 h and at room temperature for 2 h. Subsequently,all volatile components were removed under reduced pressure at roomtemperature. The crude product was used in Example 98A without furtherpurification.

Example 98A (3S)-3-Hydroxy-4-methoxy-4-oxobutanoic acid

5.17 ml (128 mmol) of methanol were added to 9.02 g (42.5 mmol) of thecompound from Example 97A, and the mixture was stirred at roomtemperature for 4 h. Subsequently, excess methanol was removed underreduced pressure and the residue was recrystallized from diethylether/cyclohexane. The solid was dried under high vacuum. This gave 5.95g (94.5% of theory) of the title compound.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.31 (br. s, 1H), 5.67 (br. s, 1H),4.38-4.31 (m, 1H), 3.63 (s, 3H), 2.63 (dd, 1H), 2.52-2.45 (m, 1H).

Example 99A Methyl (5R)-2-oxo-1,3-oxazolidine-5-carboxylate

To a solution of 5.95 g (39.4 mmol) of the compound from Example 98A in160 ml of tert-butanol were added 12.2 g (44.2 mmol) ofdiphenylphosphoryl azide and 6.16 ml (44.2 mmol) of triethylamine, andthen the mixture was heated under reflux for 4 h. The mixture was cooleddown to room temperature and the solvent was removed under reducedpressure. The residue was purified by means of flash chromatography(ethyl acetate/cyclohexane gradient). Finally, recrystallization waseffected from ethyl acetate/cyclohexane, the solid was dried under highvacuum and 3.48 g (59.7% of theory) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.79 (s, 1H), 5.15 (dd, 1H),3.80-3.74 (m, 1H), 3.73 (s, 3H), 3.52-3.46 (m, 1H).

Example 100A Ethyl7-chloro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylate

To a solution of 12.1 g (38.0 mmol) of ethyl2-[(2,6-dichloropyridin-3-yl)carbonyl]-3-ethoxyacrylate (CAS157373-27-8) and 7.83 g (53.2 mmol) of 2,4,6-trifluoroaniline in 60.5 mlof DCM were added 46.4 ml (266 mmol) of DIPEA, and the mixture wasstirred at RT for 4 h. Subsequently, 5.26 g (38.0 mmol) of potassiumcarbonate were added and the mixture was heated under reflux overnight.The mixture was diluted with 200 ml of DCM and washed twice with 150 mlof 1 M aqueous hydrochloric acid. The organic phase was dried oversodium sulphate and filtered, and the solvent was removed under reducedpressure. The suspension obtained was stirred with 80 ml of tert-butylmethyl ether, and the precipitate was filtered off with suction, washedwith 10 ml of tert-butyl methyl ether and dried under high vacuum. 8.60g (58% of theory, 99% purity) of the title compound were obtained.

LC-MS (Method 1): R_(t)=0.97 min; 383 [M+H]⁺.

Example 100B7-Chloro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid

To an initial charge of 8.60 g (22.5 mmol) of ethyl7-chloro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylate(Example 100A) in 67.7 ml of water were added 67.7 ml of 36 percentaqueous hydrochloric acid and 67.7 ml of THF, and the mixture wasstirred at 110° C. for 4.5 h. The reaction mixture was cooled down toRT. The precipitate was filtered off with suction, washed with water anddried under high vacuum. 7.87 g (98% of theory, 99% purity) of the titlecompound were obtained.

LC-MS (Method 1): R_(t)=0.95 min; MS (ESIpos): m/z=355 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6): δ [ppm]=13.83 (s, 1H), 9.27 (s, 1H), 8.78 (d,1H), 7.82 (d, 1H), 7.67-7.59 (m, 2H).

Example 100C7-Chloro-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 1.00 g (2.82 mmol) of7-chloro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid (Example 100B) were reacted with 692 mg (4.23 mmol) of(2R)-1,1,1-trifluorobutan-2-amine hydrochloride in the presence of 1.07g (2.82 mmol) of HATU and 1.18 ml (6.77 mmol) ofN,N-diisopropylethylamine in 28.3 ml of dimethylformamide. The reactionwas ended by adding 40 ml of water and 60 ml of ethyl acetate, and thephases were separated. The aqueous phase was extracted three times with20 ml of ethyl acetate, and the combined organic phases were washed with40 ml of a mixture (1:1, v/v) of saturated aqueous sodium chloridesolution and aqueous 1N hydrochloric acid. The organic phase was washedthree times with 30 ml of saturated aqueous sodium chloride solution,dried over sodium sulphate and filtered, and the solvent was removedunder reduced pressure. The residue was purified by means of normalphase chromatography (cyclohexane-ethyl acetate gradient), and 1.16 g(88% of theory; 99% purity) of the title compound were obtained.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=9.88 (d, 1H), 9.13 (s, 1H), 8.75 (d,1H), 7.78 (d, 1H), 7.66-7.58 (m, 2H), 4.83-4.72 (m, 1H), 1.95-1.84 (m,1H), 1.74-1.61 (m, 1H), 0.98 (t, 3H).

LC-MS (Method 3): R_(t)=2.35 min; 464 [M+H]⁺.

Example 101Arac-7-Chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-1-(2,4-difluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 500 mg (1.49 mmol) of7-chloro-4-oxo-1-(2,4-difluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid (Example 35A) were reacted with 391 mg (2.23 mmol) of1-cyclopropyl-2,2,2-trifluoroethanamine hydrochloride (racemate, CAS:75702-99-7) in the presence of 565 mg (1.49 mmol) of HATU and 621 μl(3.56 mmol) of N,N-diisopropylethylamine in 15 ml of dimethylformamide.The reaction was ended by adding 20 ml of water and 30 ml of ethylacetate, and the phases were separated. The aqueous phase was extractedthree times with 10 ml of ethyl acetate, and the combined organic phaseswere washed with 40 ml of a mixture (1:1, v/v) of saturated aqueoussodium chloride solution and aqueous 1N hydrochloric acid. The organicphase was washed three times with 15 ml of saturated aqueous sodiumchloride solution, dried over sodium sulphate and filtered, and thesolvent was removed under reduced pressure. The residue was purified bymeans of normal phase chromatography (cyclohexane-ethyl acetategradient), and 564 mg (82% of theory; 99% purity) of the title compoundwere obtained.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=10.14 (d, 1H), 8.89 (s, 1H), 8.75 (d,1H), 7.91-7.81 (m, 1H), 7.76 (d, 1H), 7.68-7.59 (m, 1H), 7.41-7.33 (m,1H), 4.47-4.33 (m, 1H), 1.29-1.19 (m, 1H), 0.71-0.51 (m, 3H), 0.37-0.28(m, 1H).

LC-MS (Method 1): R_(t)=1.20 min; 458 [M+H]⁺.

Example 102Arac-7-Chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-1-(2,6-difluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 1.00 g (2.97 mmol) of7-chloro-4-oxo-1-(2,6-difluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid (Example 85A) were reacted with 782 mg (4.46 mmol) of1-cyclopropyl-2,2,2-trifluoroethanamine hydrochloride (racemate, CAS:75702-99-7) in the presence of 1.13 g (2.97 mmol) of HATU and 1.24 ml(7.13 mmol) of N,N-diisopropylethylamine in 30 ml of dimethylformamide.The reaction was ended by adding 20 ml of water and 30 ml of ethylacetate, and the phases were separated. The aqueous phase was extractedthree times with 10 ml of ethyl acetate, and the combined organic phaseswere washed with 20 ml of a mixture (1:1, v/v) of saturated aqueoussodium chloride solution and aqueous 1N hydrochloric acid. The organicphase was washed three times with 15 ml of saturated aqueous sodiumchloride solution, dried over sodium sulphate and filtered, and thesolvent was removed under reduced pressure. The residue was purified bymeans of normal phase chromatography (cyclohexane-ethyl acetategradient), and 1.11 g (81% of theory; 99% purity) of the title compoundwere obtained.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=10.05 (d, 1H), 9.08 (s, 1H), 8.77 (d,1H), 7.81-7.70 (m, 2H), 7.50-7.42 (m, 2H), 4.45-4.33 (m, 1H), 1.30-1.20(m, 1H), 0.72-0.54 (m, 3H), 0.38-0.30 (m, 1H).

LC-MS (Method 3): R_(t)=2.32 min; 458 [M+H]⁺.

Example 103A7-Chloro-N-[(1R)-1-cyclopropyl-2,2,2-trifluoroethyl)-1-(2,6-difluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 1.00 g (2.94 mmol) of the compound from Example 85Awere reacted with 774 mg (4.41 mmol) of (R)-1-trifluoromethylpropylaminehydrochloride in the presence of 1.12 g (2.94 mmol) of HATU and 1.23 ml(7.06 mmol) of DIPEA in 29.5 ml of DMF. The reaction was ended by adding40 ml of water and 60 ml of ethyl acetate, and the phases wereseparated. The aqueous phase was extracted three times with 20 ml ofethyl acetate, and the combined organic phases were washed with 40 ml ofa mixture (1:1, v/v) of saturated aqueous sodium chloride solution andaqueous 1N hydrochloric acid. The organic phase was washed three timeswith 30 ml of saturated aqueous sodium chloride solution, dried oversodium sulphate and filtered, and the solvent was removed under reducedpressure. The residue was purified by means of normal phasechromatography (cyclohexane-ethyl acetate gradient), and 840 mg (62% oftheory; 99% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.05 (d, 1H), 9.08 (s, 1H), 8.76 (d,1H), 7.81-7.70 (m, 2H), 7.50-7.42 (m, 2H), 4.46-4.33 (m, 1H), 1.29-1.18(m, 1H), 0.73-0.52 (m, 3H), 0.39-0.30 (m, 1H).

LC-MS (Method 3): R_(t)=2.31 min; 458 [M+H]⁺.

Example 104A7-Chloro-N-[(1)-1-cyclopropyl-2,2,2-trifluoroethyl)-1-(2,6-difluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 350 mg (1.03 mmol) of the compound from Example 85Awere reacted with 217 mg (1.24 mmol) of (S)-1-trifluoromethylpropylaminehydrochloride in the presence of 391 mg (1.03 mmol) of HATU and 430 μl(2.47 mmol) of DIPEA in 10 ml of DMF. The mixture was poured into amixture of 30 ml of water and 5 ml of 1N aqueous hydrochloric acid, andthe precipitate was filtered off with suction. The precipitate was takenup in a little dichloromethane and purified by means of normal phasechromatography (cyclohexane-ethyl acetate gradient), and 325 mg (69% oftheory; 100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.05 (d, 1H), 9.08 (s, 1H), 8.76 (d,1H), 7.81-7.70 (m, 2H), 7.50-7.42 (m, 2H), 4.46-4.33 (m, 1H), 1.30-1.20(m, 1H), 0.72-0.53 (m, 3H), 0.39-0.29 (m, 1H).

LC-MS (Method 1): R_(t)=1.20 min; 458 [M+H]⁺.

Example 105A Ethyl7-chloro-1-(2-chloro-6-fluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate

To a solution of 6.05 g (19.0 mmol) of ethyl2-[(2,6-dichloropyridin-3-yl)carbonyl]-3-ethoxyacrylate (CAS157373-27-8) and 3.88 g (26.6 mmol) of 2-chloro-6-fluoroaniline in 30.3ml dichloromethane were added 23.2 ml (133 mmol) of DIPEA, and themixture was stirred at RT for 4 h. Subsequently, 2.63 g (19.0 mmol) ofpotassium carbonate were added and the mixture was heated under refluxovernight. The mixture was diluted with 200 ml of DCM and washed twicewith 75 ml of 1 M aqueous hydrochloric acid. The organic phase was driedover sodium sulphate and filtered, and the solvent was removed underreduced pressure. The suspension obtained was stirred with 40 ml oftert-butyl methyl ether, and the precipitate was filtered off withsuction, washed with 10 ml of tert-butyl methyl ether and dried underhigh vacuum. 5.70 g (64% of theory, 81% purity) of the title compoundwere obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.88 (s, 1H), 8.64 (d, 1H), 7.76-7.57(m, 4H), 4.25 (q, 2H), 1.28 (t, 3H).

LC-MS (Method 3): R_(t)=1.86 min; 381 [M+H]⁺.

Example 105B7-Chloro-1-(2-chloro-6-fluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid

To an initial charge of 5.70 g (14.9 mmol) of ethyl7-chloro-1-(2-chloro-6-fluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylatein 45 ml of water were added 45 ml of 36 percent aqueous hydrochloricacid and 45 ml of THF, and the mixture was stirred at 120° C. for 4.5 h.The reaction mixture was cooled down to RT. The precipitate was filteredoff with suction, washed with water and dried under high vacuum. 4.12 g(77% of theory, 99% purity) of the title compound were obtained.

¹H NMR (400 MHz, DMSO-d6): δ [ppm]=13.84 (s, 1H), 9.23 (s, 1H), 8.80 (d,1H), 7.82 (d, 1H), 7.78-7.57 (m, 3H).

LC-MS (Method 3): R_(t)=1.84 min; MS (ESIpos): m/z=352.9 [M+H]⁺.

Example 105C7-Chloro-1-(2-chloro-6-fluorophenyl)-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 1.00 g (2.83 mmol) of7-chloro-1-(2-chloro-6-fluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid were reacted with 695 mg (4.25 mmol) of(2R)-1,1,1-trifluorobutan-2-amine hydrochloride in the presence of 1.08g (2.83 mmol) of HATU and 1.18 ml (6.80 mmol) ofN,N-diisopropylethylamine in 28.4 ml of dimethylformamide. The reactionwas ended by adding 40 ml of water and 60 ml of ethyl acetate, and thephases were separated. The aqueous phase was extracted three times with20 ml of ethyl acetate, and the combined organic phases were washed with40 ml of a mixture (1:1, v/v) of saturated aqueous sodium chloridesolution and aqueous 1N hydrochloric acid. The organic phase was washedthree times with 30 ml of saturated aqueous sodium chloride solution,dried over sodium sulphate and filtered, and the solvent was removedunder reduced pressure. The residue was purified by means of normalphase chromatography (cyclohexane-ethyl acetate gradient), and 1.09 g(82% of theory; 99% purity) of the title compound were obtained.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=9.90 (d, 1H), 9.07-9.06 (m, 1H), 8.77(d, 1H), 7.79 (d, 1H), 7.77-7.57 (m, 3H), 4.83-4.71 (m, 1H), 1.96-1.84(m, 1H), 1.75-1.62 (m, 1H), 1.02-0.95 (m, 3H).

LC-MS (Method 1): R_(t)=1.31 min; 462 [M+H]⁺.

Example 106A7-Chloro-1-(2,6-difluorophenyl)-4-oxo-N-[(2S)-1,1,1-trifluoroprop-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 880 mg (2.61 mmol) of the compound from Example 85Awere reacted with 443 mg (3.92 mmol) of(2S)-1,1,1-trifluoropropan-2-amine in the presence of 994 mg (2.61 mmol)of HATU and 1.09 ml (6.27 mmol) of DIPEA in 26.4 ml of DMF. The reactionwas ended by adding 20 ml of water and 30 ml of ethyl acetate, and thephases were separated. The aqueous phase was extracted three times with10 ml of ethyl acetate, and the combined organic phases were washed with20 ml of a mixture (1:1, v/v) of saturated aqueous sodium chloridesolution and aqueous 1N hydrochloric acid. The organic phase was washedthree times with 15 ml of saturated aqueous sodium chloride solution,dried over sodium sulphate and filtered, and the solvent was removedunder reduced pressure. The crude product was purified by means of flashchromatography (cyclohexane/ethyl acetate gradient), and 773 mg (68% oftheory; 99% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=9.94 (d, 1H), 9.08 (s, 1H), 8.75 (d,1H), 7.80-7.71 (m, 2H), 7.50-7.43 (m, 2H), 4.99-4.88 (m, 1H), 1.40 (d,3H).

LC-MS (Method 3): R_(t)=2.19 min; 432 [M+H]⁺.

Example 107A7-Chloro-1-(2,4,6-trifluorophenyl)-4-oxo-N-[(2S)-1,1,1-trifluoropropan-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 1.00 g (2.82 mmol) of the compound from Example 100Bwere reacted with 478 mg (4.23 mmol) of(2S)-1,1,1-trifluoropropan-2-amine in the presence of 1.07 g (2.82 mmol)of HATU and 1.18 ml (6.77 mmol) of DIPEA in 28.5 ml of DMF. The reactionwas ended by adding 25 ml of water and 35 ml of ethyl acetate, and thephases were separated. The aqueous phase was extracted three times with15 ml of ethyl acetate, and the combined organic phases were washed with25 ml of a mixture (1:1, v/v) of saturated aqueous sodium chloridesolution and aqueous 1N hydrochloric acid. The organic phase was washedthree times with 20 ml of saturated aqueous sodium chloride solution,dried over sodium sulphate and filtered, and the solvent was removedunder reduced pressure. The crude product was purified by means of flashchromatography (cyclohexane/ethyl acetate gradient), and 751 mg (59% oftheory; 99% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=9.93 (d, 1H), 9.13 (s, 1H), 8.75 (d,1H), 7.78 (d, 1H), 7.66-7.58 (m, 2H), 5.00-4.86 (m, 1H), 1.40 (d, 3H).

LC-MS (Method 1): R_(t)=1.26 min; 450 [M+H]⁺.

Example 108A Ethyl7-chloro-1-(2-chloro-4,6-difluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate

To a solution of 13.8 g (43.4 mmol) of ethyl2-[(2,6-dichloropyridin-3-yl)carbonyl]-3-ethoxyacrylate (CAS157373-27-8) and 9.93 g (60.7 mmol) of 2-chloro-4,6-difluoroaniline in68.2 ml of dichloromethane were added 52.9 ml (304 mmol) of DIPEA, andthe mixture was stirred at RT for 4 h. Subsequently, 6.00 g (43.4 mmol)of potassium carbonate were added and the mixture was heated underreflux overnight. The mixture was diluted with 600 ml of DCM and washedtwice with 200 ml of 1 M aqueous hydrochloric acid. The organic phasewas dried over sodium sulphate and filtered, and the solvent was removedunder reduced pressure. The suspension obtained was stirred with 80 mlof tert-butyl methyl ether, and the precipitate was filtered off withsuction, washed with 20 ml of tert-butyl methyl ether and dried underhigh vacuum. 15.0 g (72% of theory, 83% purity) of the title compoundwere obtained.

LC-MS (Method 3): R_(t)=1.91 min; 399 [M+H]⁺.

Example 108B7-Chloro-1-(2-chloro-4,6-difluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid

To an initial charge of 15.0 g (37.6 mmol) of ethyl7-chloro-1-(2-chloro-4,6-difluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylatein 131 ml of water were added 131 ml of 36 percent aqueous hydrochloricacid and 131 ml of THF, and the mixture was stirred at 110° C. for 4.5h. The reaction mixture was cooled down to RT. The precipitate wasfiltered off with suction, washed with water and dried under highvacuum. 10.2 g (72% of theory, 99% purity) of the title compound wereobtained.

¹H NMR (400 MHz, DMSO-d6): δ [ppm]=13.81 (s, 1H), 9.25 (s, 1H), 8.80 (d,1H), 7.84-7.73 (m, 3H).

LC-MS (Method 3): R_(t)=1.87 min; MS (ESIpos): m/z=370.9 [M+H]⁺.

Example 108C7-Chloro-1-(2-chloro-4,6-difluorophenyl)-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 1.00 g (2.69 mmol) of7-chloro-1-(2-chloro-4,6-difluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid were reacted with 513 mg (4.04 mmol) of(2S)-1,1,1-trifluorobutan-2-amine hydrochloride in the presence of 1.02g (2.69 mmol) of HATU and 657 μl (3.77 mmol) ofN,N-diisopropylethylamine in 27 ml of dimethylformamide. The reactionwas ended by adding 40 ml of water and 60 ml of ethyl acetate, and thephases were separated. The aqueous phase was extracted three times with20 ml of ethyl acetate, and the combined organic phases were washed with40 ml of a mixture (1:1, v/v) of saturated aqueous sodium chloridesolution and aqueous 1N hydrochloric acid. The organic phase was washedthree times with 30 ml of saturated aqueous sodium chloride solution,dried over sodium sulphate and filtered, and the solvent was removedunder reduced pressure. The residue was purified by means of normalphase chromatography (cyclohexane-ethyl acetate gradient), and 914 mg(71% of theory; 100% purity) of the title compound were obtained.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=9.88 (d, 1H), 9.11 (s, 1H), 8.77 (d,1H), 7.81-7.72 (m, 3H), 4.83-4.71 (m, 1H), 1.96-1.84 (m, 1H), 1.74-1.61(m, 1H), 1.01-0.94 (m, 3H).

LC-MS (Method 3): R_(t)=2.40 min; 480 [M+H]⁺.

Example 109A7-Chloro-1-(2-chloro-4,6-difluorophenyl)-4-oxo-N-(4,4,4-trifluoro-2-methylbutan-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 255 mg (680 μmol) of7-chloro-1-(2-chloro-4,6-difluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid were reacted with 181 mg (1.02 mmol) of4,4,4-trifluoro-2-methylbutan-2-amine hydrochloride in the presence of259 mg (680 μmol) of HATU and 415 μl (2.38 mmol) ofN,N-diisopropylethylamine in 7 ml of dimethylformamide. The reactionmixture was adjusted to pH 1 with 1N aqueous hydrochloric acid andpurified in several runs by means of preparative HPLC (column:Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05% formicacid gradient (0 to 3 min 15% acetonitrile, to 15 min 90% acetonitrileand for a further 3 min 90% acetonitrile). 202 mg (60% of theory, 100%purity) of the title compound were obtained.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=9.70 (s, 1H), 9.00 (s, 1H), 8.75 (d,1H), 7.80-7.72 (m, 3H), 3.03-2.89 (m, 2H), 1.50 (s, 6H).

LC-MS (Method 3): R_(t)=2.41 min; 494 [M+H]⁺.

Example 110A7-Chloro-1-(2-chloro-4,6-difluorophenyl)-N-[(15)-1-cyclopropyl-2,2,2-trifluoroethyl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 600 mg (1.62 mmol) of7-chloro-1-(2-chloro-4,6-difluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid were reacted with 426 mg (2.43 mmol) of(1S)-1-cyclopropyl-2,2,2-trifluoroethanamine hydrochloride in thepresence of 615 mg (1.62 mmol) of HATU and 676 μl (3.88 mmol) ofN,N-diisopropylethylamine in 16.2 ml of dimethylformamide. The reactionmixture was stirred into a mixture of 200 ml of water and 16 ml of 1Naqueous hydrochloric acid, and the precipitate was filtered off withsuction. The precipitate was taken up in a little dichloromethane andpurified by means of normal phase chromatography (cyclohexane-ethylacetate gradient). 633 mg (79% of theory, 99% purity) of the titlecompound were obtained.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=10.05 (d, 1H), 9.11 (s, 1H), 8.78 (d,1H), 7.81-7.72 (m, 3H), 4.46-4.32 (m, 1H), 1.30-1.19 (m, 1H), 0.71-0.53(m, 3H), 0.40-0.29 (m, 1H).

LC-MS (Method 1): R_(t)=1.23 min; 492 [M+H]⁺.

Example 111A7-Chloro-1-(2-chloro-4,6-difluorophenyl)-4-oxo-N-[(2S)-1,1,1-trifluoroprop-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 5.00 g (13.5 mmol) of7-chloro-1-(2-chloro-4,6-difluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid were reacted with 1.83 g (16.2 mmol) of(2S)-1,1,1-trifluoropropan-2-amine hydrochloride in the presence of 5.12g (13.5 mmol) of HATU and 5.63 ml (32.3 mmol) ofN,N-diisopropylethylamine in 135 ml of dimethylformamide. The reactionmixture was stirred into a mixture of 600 ml of water and 135 ml of 1Naqueous hydrochloric acid, and the precipitate was filtered off withsuction. The precipitate was taken up in 12 ml of dichloromethane andpurified by means of normal phase chromatography (cyclohexane-ethylacetate gradient). 4.12 g (65% of theory, 99% purity) of the titlecompound were obtained.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=9.94 (d, 1H), 9.11 (d, 1H), 8.76 (d,1H), 7.81-7.72 (m, 3H), 4.98-4.86 (m, 1H), 1.42-1.38 (m, 3H).

LC-MS (Method 1): R_(t)=1.21 min; 466 [M+H]⁺.

Example 112A7-Chloro-1-(2-chloro-4,6-difluorophenyl)-4-oxo-N-[(2S)-1-(trifluoromethoxy)propan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 264 mg (704 μmol) of7-chloro-1-(2-chloro-4,6-difluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid were reacted with 190 mg (1.06 mmol) of(2S)-1-(trifluoromethoxy)propan-2-amine hydrochloride in the presence of268 mg (704 μmol) of HATU and 294 μl (1.69 mmol) ofN,N-diisopropylethylamine in 7 ml of dimethylformamide. The reactionmixture was stirred into a mixture of 42 ml of water and 6 ml of 1Naqueous hydrochloric acid, and the precipitate was filtered off withsuction. The precipitate was taken up in dichloromethane, the phaseswere separated, the organic phase was dried over magnesium sulphate andfiltered and the solvent was removed under reduced pressure. The residuewas purified by means of normal phase chromatography (cyclohexane-ethylacetate gradient), and 299 mg (86% of theory; 100% purity) of the titlecompound were obtained.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=9.76-9.61 (m, 1H), 9.03 (s, 1H), 8.76(d, 1H), 7.80-7.72 (m, 3H), 4.43-4.31 (m, 1H), 4.24-4.14 (m, 2H),1.30-1.22 (m, 3H).

LC-MS (Method 3): R_(t)=2.32 min; 496 [M+H]⁺.

Example 113A4-Oxo-7-(2-oxoimidazolidin-1-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid

According to GP2, 15.0 g (42.3 mmol) of the compound from Example 100Bwere reacted with 25.5 g (296 mmol) of imidazolin-2-one in the presenceof 14.6 g (106 mmol) of potassium carbonate, 190 mg (846 μmol) ofpalladium(II) acetate and 979 mg (1.69 mmol) of Xantphos in 400 ml of1,4-dioxane. The mixture was stirred at 90° C. for 2.5 h and then cooleddown to RT. The suspension was stirred into water and adjusted to pH 2with dilute aqueous hydrochloric acid. The precipitate was filtered offwith suction and washed with water. The residue was stirred inacetonitrile, filtered off with suction, washed and dried under highvacuum. This gave 15.0 g (88% of theory) of the title compound.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=14.7 (s, 1H), 9.20 (s, 1H), 8.63-8.47(m, 2H), 7.75 (s, 1H), 7.64-7.54 (m, 2H), 3.64-3.55 (m, 2H).

LC-MS (Method 3): R_(t)=1.37 min; 405 [M+H]⁺.

Example 114A7-Chloro-1-(2,6-difluorophenyl)-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 1.00 g (2.97 mmol) of the compound from Example 85Awere reacted with 566 mg (4.46 mmol) of(2S)-1,1,1-trifluorobutan-2-amine in the presence of 1.13 g (2.97 mmol)of HATU and 1.24 ml (7.13 mmol) of N,N-diisopropylethylamine in 30 ml ofdimethylformamide. The reaction mixture was diluted with 20 ml of waterand 30 ml of ethyl acetate, and the phases were separated. The aqueousphase was extracted three times with 10 ml of ethyl acetate, and thecombined organic phases were washed with 20 ml of a mixture of 1Naqueous hydrochloric acid and saturated aqueous ammonium chloridesolution. This was followed by washing three times with 15 ml ofsaturated aqueous sodium chloride solution, drying over sodium sulphateand filtration, and removal of the solvent under reduced pressure. Theresidue was taken up in 10 ml of dichloromethane and purified by meansof normal phase chromatography (cyclohexane-ethyl acetate gradient). 884mg (66% of theory, 99% purity) of the title compound were obtained.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=9.89 (d, 1H), 9.09 (s, 1H), 8.76 (d,1H), 7.80-7.71 (m, 2H), 7.50-7.43 (m, 2H), 4.84-4.70 (m, 1H), 1.96-1.84(m, 1H), 1.75-1.61 (m, 1H), 0.98 (t, 3H).

LC-MS (Method 1): R_(t)=1.20 min; MS (ESIpos) m/z 446 [M+H]⁺.

Example 115A7-Chloro-1-(2,4,6-trifluorophenyl)-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 2.00 g (5.64 mmol) of the compound from Example 100Bwere reacted with 1.11 g (6.77 mmol) of(2S)-1,1,1-trifluorobutan-2-amine in the presence of 2.14 g (5.64 mmol)of HATU and 3.34 ml (19.2 mmol) of N,N-diisopropylethylamine in 57 ml ofdimethylformamide. The reaction mixture was diluted with 75 ml of waterand 100 ml of ethyl acetate, and the phases were separated. The aqueousphase was extracted three times with 50 ml of ethyl acetate, and thecombined organic phases were washed with 60 ml of a mixture of 1Naqueous hydrochloric acid and saturated aqueous ammonium chloridesolution. This was followed by washing three times with 20 ml ofsaturated aqueous sodium chloride solution, drying over magnesiumsulphate and filtration, and removal of the solvent under reducedpressure. The residue was taken up in dichloromethane and purified bymeans of normal phase chromatography (cyclohexane-ethyl acetategradient). 1.28 g (49% of theory, 100% purity) of the title compoundwere obtained.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=9.88 (d, 1H), 9.13 (s, 1H), 8.75 (d,1H), 7.78 (m, 1H), 7.66-7.58 (m, 2H), 4.84-4.71 (m, 1H), 1.96-1.84 (m,1H), 1.74-1.62 (m, 1H), 0.98 (t, 3H).

LC-MS (Method 3): R_(t)=2.30 min; MS (ESIpos) m/z 464 [M+H]⁺.

Example 116A (3S,5R)-3,5-Dimethylpyrrolidin-3-ol trifluoroacetic acid

To a solution of 100 mg (464 μmol) of tert-butyl(2R,4S)-4-hydroxy-2,4-dimethylpyrrolidine-1-carbamate in 1.5 ml ofdichloromethane were added 500 μl (6.49 mmol) of trifluoroacetic acid,and the mixture was stirred at room temperature for 2 h. The solvent wasremoved under reduced pressure and the residue was coevaporated threetimes with 5 ml of dichloromethane. 98.6 mg (88% of theory, 95% purity)of the title compound were obtained.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=9.10 (br. s, 1H), 8.68 (br. s, 1H),5.22 (br. s, 1H), 3.76-3.63 (m, 1H), 3.10-3.03 (m, 1H), 3.00-2.91 (m,1H), 2.12 (dd, 1H), 1.62 (ddd, 1H), 1.34 (d, 3H), 1.32 (s, 3H).

Example 117A7-[(4S)-4-Hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid

According to GP2, 50.0 g (141 mmol) of the compound from Example 100Bwere reacted with 17.1 g (169 mmol) of (4S)-4-hydroxypyrrolidin-2-one inthe presence of 29.2 g (211 mmol) of potassium carbonate, 6.33 g (28.2mmol) of palladium(II) acetate and 16.3 g (28.2 mmol) of Xantphos in1000 ml of 1,4-dioxane at 80° C. for 1.5 h. The mixture was cooled downand extracted by stirring in a mixture of ice-water, hydrochloric acidand ethyl acetate. The mixture was filtered with suction throughkieselguhr, and the organic phase was washed with water and saturatedaqueous sodium chloride solution, dried and finally concentrated. Theresidue was admixed with acetonitrile, cooled and filtered off withsuction, and the precipitate was washed with cold acetonitrile. 48 g(81% of theory, 97% purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.33 min; MS (ESIpos) m/z 420 [M+H]⁺.

Example 118A7-Chloro-1-(2,4,6-trifluorophenyl)-4-oxo-N-[(2S)-1-(trifluoromethoxy)propan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 250 mg (698 μmol) of the compound from Example 100Bwere reacted with 188 mg (1.05 mmol) of(2S)-1-(trifluoromethoxy)propan-2-amine hydrochloride in the presence of265 mg (698 μmol) of HATU and 292 μl (1.68 mmol) ofN,N-diisopropylethylamine in 7 ml of dimethylformamide. The reactionmixture was stirred into a mixture of 42 ml of water and 6 ml of 1Naqueous hydrochloric acid, and the precipitate was filtered off withsuction. The precipitate was taken up in dichloromethane, the phaseswere separated, the organic phase was dried over magnesium sulphate andfiltered and the solvent was removed under reduced pressure. The residuewas purified by means of normal phase chromatography (cyclohexane-ethylacetate gradient), and 226 mg (68% of theory; 100% purity) of the titlecompound were obtained.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=9.63 (d, 1H), 9.06 (s, 1H), 8.74 (d,1H), 7.76 (d, 1H), 7.65-7.57 (m, 2H), 4.43-4.32 (m, 1H), 4.24-4.15 (m,2H), 1.26 (d, 3H).

LC-MS (Method 1): R_(t)=1.21 min; MS (ESIpos) m/z 480 [M+H]⁺.

Example 119A7-Chloro-1-(2-chloro-6-fluorophenyl)-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 500 mg (1.42 mmol) of the compound from Example 105Bwere reacted with 347 mg (2.12 mmol) of(2S)-1,1,1-trifluorobutan-2-amine hydrochloride in the presence of 538mg (1.42 mmol) of HATU and 592 μl (3.40 mmol) ofN,N-diisopropylethylamine in 14.2 ml of dimethylformamide. The reactionmixture was stirred into a solution of 50 ml of water and 15 ml of 1Naqueous hydrochloric acid, and the precipitate was filtered off withsuction, washed with water and dried. The precipitate was dissolved in10 ml of dichloromethane and purified by means of normal phasechromatography (cyclohexane-ethyl acetate gradient). 496 mg (75% oftheory, 99% purity) of the title compound were obtained.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=9.90 (d, 1H), 9.07 (s, 1H), 8.77 (d,1H), 7.81-7.56 (m, 4H), 4.84-4.70 (m, 1H), 1.96-1.83 (m, 1H), 1.76-1.62(m, 1H), 1.02-0.94 (m, 3H).

LC-MS (Method 3): R_(t)=2.33 min; 462 [M+H]⁺.

Example 120A7-Chloro-1-(2-chloro-6-fluorophenyl)-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 250 mg (708 μmol) of the compound from Example 105Bwere reacted with 186 mg (1.06 mmol) of(1S)-1-cyclopropyl-2,2,2-trifluoroethanamine hydrochloride in thepresence of 269 mg (708 μmol) of HATU and 296 μl (1.70 mmol) ofN,N-diisopropylethylamine in 7.1 ml of dimethylformamide. The reactionmixture was stirred into a solution of 25 ml of water and 8 ml of 1Naqueous hydrochloric acid, and the precipitate was filtered off withsuction, washed with water and dried. The precipitate was dissolved in 8ml of dichloromethane and purified by means of normal phasechromatography (cyclohexane-ethyl acetate gradient). 250 mg (74% oftheory, 99% purity) of the title compound were obtained.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=10.06 (d, 1H), 9.06 (s, 1H), 8.78 (d,1H), 7.79 (d, 1H), 7.77-7.57 (m, 3H), 4.45-4.32 (m, 1H), 1.31-1.20 (m,1H), 0.73-0.53 (m, 3H), 0.40-0.30 (m, 1H).

LC-MS (Method 3): R_(t)=2.35 min; 474 [M+H]⁺.

Example 121A7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid

According to GP3, 10.0 g (28.2 mmol) of the compound from Example 100Bwere reacted with 4.46 g (31.0 mmol, 97% purity) of(3R,4R)-pyrrolidine-3,4-diol hydrochloride and 17.2 ml (98.7 mmol) ofN,N-diisopropylethylamine in 150 ml of dimethylformamide. The mixturewas diluted with 350 ml of water, 150 ml of 1N aqueous hydrochloric acidand 250 ml of ethyl acetate. The phases were separated and the aqueousphase was extracted three times with 250 ml of ethyl acetate. Thecombined organic phases were washed twice with 250 ml of phosphatebuffer solution (3.52 g potassium dihydrogenphosphate, 7.26 g ofdisodium hydrogenphosphate dihydrate in 1000 ml of water, pH 7) and 250ml of saturated aqueous sodium chloride solution, dried over magnesiumsulphate, filtered and concentrated to a volume of about 100 ml. 250 mlof tert-butyl methyl ether were slowly added dropwise while stirring.The precipitate was filtered off with suction and dried under highvacuum. 10.8 g (91% of theory, 100% by LC/MS) of the title compound wereobtained. By NMR, the product still contained traces of ethyl acetate,but was used without further purification.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=15.23 (s, 1H), 9.02 (s, 1H), 8.30 (d,1H), 7.62-7.54 (m, 2H), 6.87 (d, 1H), 5.26 (d, 1H), 5.17 (d, 1H), 4.06(br. s, 1H, partly beneath a resonance of ethyl acetate), 3.94 (br. s,1H), 3.64 (dd, 1H), 3.37 (d, 1H), 3.27 (dd, 1H), 3.08 (d, 1H).

LC-MS (Method 3): R_(t)=1.68 min; m/z=563 [M+H]⁺.

Example 122A 1-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)imidazolidin-2-one

To a solution of 1.00 g (7.68 mmol) of1-(2-hydroxyethyl)imidazolidin-2-one (CAS: 3699-54-5) and 628 mg (9.22mmol) of imidazole in 7.75 ml of dimethylformamide at 0° C. were added1.27 g (8.45 mmol) of tert-butyldimethylsilyl chloride, and the mixturewas stirred at room temperature overnight. All volatile constituentswere removed under reduced pressure and 10 ml of water were added to theresidue. The mixture was extracted three times with 20 ml of ethylacetate. The combined organic phases were washed with saturated aqueoussodium chloride solution, dried over magnesium sulphate and filtered,and the solvent was removed under reduced pressure. 1.24 g (66% oftheory, 100% purity) of the title compound were obtained.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=6.24 (br. s, 1H), 3.64 (t, 2H),3.41-3.36 (m, 2H), 3.22-3.17 (m, 2H), 3.11 (t, 2H), 0.86 (s, 9H), 0.04(s, 6H).

LC-MS (Method 3): R_(t)=1.78 min; m/z=245 [M+H]⁺.

Example 123A7-[3-(2-Hydroxyethyl)-2-oxoimidazolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid

According to General Procedure 2, 250 mg (705 μmol) of the compound fromExample 100B were reacted with 190 mg (775 μmol) of the compound fromExample 122A in the presence of 244 mg (1.76 mmol) of potassiumcarbonate, 7.9 mg (35 μmol) of palladium(II) acetate and 41 mg (70 μmol)of Xantphos in 10 ml of dioxane at 90° C. for 90 min. The reactionmixture was poured into 15 ml of aqueous 1N hydrochloric acid and 15 mlof saturated aqueous sodium chloride solution and stirred. The mixturewas extracted twice with 50 ml of ethyl acetate and the combined organicphases were concentrated. The residue was purified in three runs bymeans of preparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm,solvent: acetonitrile/0.1% formic acid gradient; 0 to 5 min 10%acetonitrile, over 14 min to 90% acetonitrile and for a further 4 min90% acetonitrile). The collected fractions of the silylated intermediatewere admixed again with 10 ml of aqueous 1N hydrochloric acid andstirred at 40° C. for 30 minutes. This was followed by concentration andseparation of the residue in three runs by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.1%formic acid gradient; 0 to 5 min 10% acetonitrile, over 14 min to 90%acetonitrile and for a further 4 min 90% acetonitrile). The productfractions were combined and 269 mg (85% of theory, 100% purity) of thetitle compound were obtained.

¹H NMR (400 MHz, DMSO-d6): δ [ppm]=14.66 (br. s, 1H), 9.20 (s, 1H), 8.61(d, 1H), 8.51 (d, 1H), 7.64-7.56 (m, 2H), 4.75 (br. s, 1H), 3.58-3.46(m, 6H), 3.28 (t, 2H).

LC-MS (Method 3): R_(t)=1.18 min; MS (ESIpos): m/z=449 [M+H]⁺.

Example 124A1-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)tetrahydropyrimidin-2(1H)-one

To a solution of 600 mg (4.16 mmol) of1-(2-hydroxyethyl)tetrahydropyrimidin-2(1H)-one (DE1121617, 1962) and690 mg (4.58 mmol) of tert-butyl(chloro)dimethylsilane in 4.2 ml of DMFwere added, at 0° C., 340 mg (4.99 mmol) of imidazole. The mixture wasstirred at 0° C. for 30 min and at RT overnight. Subsequently, allvolatile constituents were removed under reduced pressure and theresidue was admixed with 10 ml of water and extracted three times with20 ml of ethyl acetate. The combined organic phases were washed with 30ml of saturated aqueous sodium chloride solution, dried with magnesiumsulphate and filtered, and the solvent was removed under reducedpressure. 732 mg (68% of theory, 100% purity) of the title compound wereobtained.

¹H NMR (400 MHz, DMSO-d6): δ [ppm]=6.11 (s, 1H), 3.63 (t, 2H), 3.30-3.21(m, 4H), 3.11-3.04 (m, 2H), 1.80-1.72 (m, 2H), 0.86 (s, 9H), 0.03 (s,6H).

LC-MS (Method 3): R_(t)=1.83 min; MS (ESIpos): m/z=259 [M+H]⁺.

Example 125A7-[3-(2-Hydroxyethyl)-2-oxotetrahydropyrimidin-1(2H)-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid

According to General Procedure 2, 250 mg (705 μmol) of the compound fromExample 100B were reacted with 166 mg (641 μmol) of the compound fromExample 124A in the presence of 221 mg (1.60 mmol) of potassiumcarbonate, 7.2 mg (32 μmol) of palladium(II) acetate and 37 mg (64 μmol)of Xantphos in 6.4 ml of dioxane at 90° C. for 90 min. The reactionmixture was diluted with 15 ml of dioxane, poured into 15 ml of aqueous1N hydrochloric acid and 15 ml of saturated aqueous sodium chloridesolution and stirred at 40° C. The mixture was extracted three timeswith 30 ml of ethyl acetate and the combined organic phases wereconcentrated. The residue was purified in two runs by means ofpreparative HPLC (column: Chromatorex C18, 10 m, 125×30 mm, solvent:acetonitrile/0.1% formic acid gradient; 0 to 5 min 10% acetonitrile,over 14 min to 90% acetonitrile and for a further 4 min 90%acetonitrile). 110 mg (26% of theory, 78% purity) of the title compoundwere obtained.

¹H NMR (400 MHz, DMSO-d6): δ [ppm]=14.61 (br. s, 1H), 9.22 (s, 1H), 8.55(d, 1H), 8.24 (d, 1H), 7.65-7.57 (m, 2H), 4.71 (t, 1H), 3.58-3.48 (m,4H), 3.42-3.36 (m, 4H), 1.95-1.86 (m, 2H).

LC-MS (Method 3): R_(t)=1.36 min; MS (ESIpos): m/z=463 [M+H]⁺.

Example 126A7-Chloro-N-[(15)-1-cyclopropyl-2,2,2-trifluoroethyl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 2.00 g (5.64 mmol) of the compound from Example 100Bwere reacted with 1.09 g (6.20 mmol) of(1S)-1-cyclopropyl-2,2,2-trifluoroethanamine hydrochloride in thepresence of 2.14 g (5.64 mmol) of HATU and 2.36 ml (13.5 mmol) ofN,N-diisopropylethylamine in 50 ml of dimethylformamide. The mixture wasstirred at room temperature for a further 5 min and then the reactionmixture was poured into 20 ml of water. 3 ml of 1N aqueous hydrochloricacid were added, and the precipitate was filtered off with suction andwashed with water. The residue was taken up in 10 ml of dichloromethaneand purified by means of normal phase chromatography (cyclohexane-ethylacetate gradient). 1.82 g (68% of theory, 100% purity) of the titlecompound were obtained.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=10.04 (d, 1H), 9.13 (s, 1H), 8.76 (d,1H), 7.79 (d, 1H), 7.65-7.58 (m, 2H), 4.46-4.33 (m, 1H), 1.30-1.19 (m,1H), 0.73-0.52 (m, 3H), 0.38-0.29 (m, 1H).

LC-MS (Method 3): R_(t)=2.31 min; MS (ESIpos) m/z 476 [M+H]⁺.

Example 127A 7-(5-Benzyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)-N-[(1S)-cyclopropyl-2,2,2-trifluoroethyl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 100 mg (210 μmol) of the compound from Example 126Awere reacted with 53.5 mg (252 μmol) of 2-benzyl-1,2,5-thiadiazolidine1,1-dioxide in the presence of 43.6 mg (315 μmol) of potassiumcarbonate, 4.7 mg (21 μmol) of palladium(II) acetate and 24 mg (42 μmol)of Xantphos in 1.5 ml of 1,4-dioxane. Subsequently, the volume of themixture was reduced under reduced pressure, and the residue was taken upwith 1 ml of aqueous 1N hydrochloric acid and 1 ml of acetonitrile andseparated by means of preparative HPLC (column: Chromatorex C18, 10 μm,125×30 mm, solvent: acetonitrile/0.1% formic acid gradient; 0 to 5 min10% acetonitrile, over 14 min to 90% acetonitrile and for a further 4min 90% acetonitrile). The product fractions were combined and 104 mg(75% of theory, 98.5% purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=2.39 min; MS (ESIpos) m/z 652 [M+H]⁺.

Example 128A7-[(2-Aminoethyl)amino]-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamidehydrochloride

To a solution of 500 mg (1.08 mmol) of the compound from Example 115A in11 ml of dimethylformamide were added 1.44 ml (21.6 mmol) ofethane-1,2-diamine. The mixture was stirred at room temperature for afurther 45 min. The mixture was concentrated by rotary evaporation andtaken up with 6 ml of aqueous hydrochloric acid and 4 ml ofacetonitrile, and purified in two runs by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, eluent: acetonitrile/0.1%formic acid gradient; 0 to 5 min 10% acetonitrile, over 14 min to 90%acetonitrile and for a further 4 min 90% acetonitrile). 426 mg (81% oftheory, 100% purity) of the title compound were obtained. The yield isbased on the free amine.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=10.44 (d, 1H), 8.79 (s, 1H), 8.38 (br.s, 1H), 8.30 (s, 1H), 8.19 (d, 1H), 7.58-7.50 (m, 2H), 6.73 (d, 1H),4.80-4.66 (m, 1H), 3.15-3.03 (m, 2H), 2.71-2.59 (m, 2H), 1.95-1.80 (m,1H), 1.71-1.56 (m, 1H), 0.96 (t, 3H).

LC-MS (Method 1): R_(t)=0.67 min; MS (ESIpos) m/z 488 [M+H]⁺.

Example 129A Ethyl7-({(2R)-2-[(tert-butoxycarbonyl)amino]propyl}amino)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylate

To a solution of 1.50 g (3.92 mmol) of the compound from Example 100A in25 ml of dimethylformamide were successively added 991 mg (4.70 mmol) oftert-butyl [(2R)-1-aminopropan-2-yl]carbamate hydrochloride and 2.39 ml(13.7 mmol) of N,N-diisopropylethylamine. The mixture was stirred atroom temperature overnight and at 60° C. for 37 h. Subsequently, thereaction solution was poured into 250 ml of water and adjusted to pH 5with aqueous 1N hydrochloric acid. The precipitate was filtered off withsuction, washed with water and dried under high vacuum. 1.81 g (85% oftheory, 95% purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.82 min; MS (ESIpos) m/z 521 [M+H]⁺.

Example 129B Ethyl7-{[(2R)-2-aminopropyl]amino}-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylatetrifluoroacetate

To a solution of 1.80 g (3.46 mmol) of the compound from Example 129A in100 ml of dichloromethane were added 5.33 ml (69.2 mmol) oftrifluoroacetic acid. The mixture was stirred at room temperature for afurther 2.5 h. Subsequently, all volatile constituents were removedunder reduced pressure and the residue was codistilled with toluene andlyophilized. 2.50 g (quantitative, 99% purity) of the title compoundwere obtained.

LC-MS (Method 3): R_(t)=0.92 min; MS (ESIpos) m/z 421 [M+H]⁺.

Example 129C Ethyl7-[(4R)-4-methyl-2-oxoimidazolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylate

To a solution of 2.50 g (4.68 mmol) of the compound from Example 129B in03 ml of dimethylformamide were successively added 647 mg (4.68 mmol) ofpotassium carbonate and 1.90 g (11.7 mmol) of 1,1′-carbonyldiimidazole.The mixture was stirred at room temperature for a further 6 h. Thereaction solution was poured into 600 ml of water, and 5 ml of aqueous1N hydrochloric acid were added. The precipitate was filtered off withsuction, washed with water and dried under high vacuum. 1.20 g (59% oftheory, 99% purity) of the title compound were obtained.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=8.79 (s, 1H), 8.44 (d, 1H), 8.34 (d,1H), 7.76 (s, 1H), 7.63-7.53 (m, 2H), 4.23 (q, 2H), 3.80-3.67 (m, 2H),3.12-3.02 (m, 1H), 1.28 (t, 3H), 1.12 (d, 3H).

LC-MS (Method 1): R_(t)=0.86 min; MS (ESIpos) m/z 447 [M+H]⁺.

Example 129D7-[(4R)-4-Methyl-2-oxoimidazolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid

To an initial charge of 1.19 g (2.67 mmol) of the compound from Example129C in 8 ml of water were added 8 ml of 36 percent aqueous hydrochloricacid and 8 ml of THF, and the mixture was stirred at 110° C. for 3 h.The reaction mixture was cooled to RT and 100 ml of water were added.The precipitate was filtered off with suction, washed with water anddried under high vacuum. 994 mg (87% of theory, 97% purity) of the titlecompound were obtained.

LC-MS (Method 3): R_(t)=1.49 min; MS (ESIpos): m/z=419 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6): δ [ppm]=14.65 (s, 1H), 9.19 (s, 1H), 8.60 (d,1H), 8.50 (d, 1H), 7.91 (s, 1H), 7.65-7.55 (m, 2H), 3.81-3.70 (m, 2H),3.13-3.07 (m, 1H), 1.13 (d, 3H).

Example 130A Ethyl7-chloro-1-(2,6-dichloro-4-fluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate

To a solution of 6.07 g (19.1 mmol) of ethyl2-[(2,6-dichloropyridin-3-yl)carbonyl]-3-ethoxyacrylate (CAS157373-27-8) and 4.81 g (26.7 mmol) of 2,6-dichloro-4-fluoroaniline in30 ml DCM were added 23.3 ml (134 mmol) of DIPEA, and the mixture wasstirred at RT for 4 h. Subsequently, 2.64 g (19.1 mmol) of potassiumcarbonate were added and the mixture was heated under reflux overnight.The mixture was diluted with 200 ml of DCM and washed twice with 75 mlof 1 M aqueous hydrochloric acid. The organic phase was dried oversodium sulphate and filtered, and the solvent was removed under reducedpressure. The suspension obtained was stirred with 40 ml of tert-butylmethyl ether, and the precipitate was filtered off with suction, washedwith 10 ml of tert-butyl methyl ether and dried under high vacuum. 3.81g (45% of theory, 94% purity) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.04 min; MS (ESIpos) m/z 415 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6): δ [ppm]=8.88 (s, 1H), 8.65 (d, 1H), 7.92 (d,2H), 7.69 (d, 1H), 4.25 (q, 2H), 1.28 (t, 3H).

Example 130B7-Chloro-1-(2,6-dichloro-4-fluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthridine-3-carboxylicacid

To an initial charge of 3.81 g (8.62 mmol, 94% purity) of the compoundfrom Example 130A in 38 ml of water were added 38 ml of 36 percentaqueous hydrochloric acid and 38 ml of THF, and the mixture was stirredat 110° C. for 4.5 h. The reaction mixture was cooled to RT and dilutedwith 200 ml of water. The precipitate was filtered off with suction,washed with water and dried under high vacuum. 3.36 g (quantitative,100% purity) of the title compound were obtained.

LC-MS (Method §): R_(t)=1.96 min; MS (ESIpos): m/z=387 [M+H]⁺.

Example 130C7-Chloro-N-[(1R)-1-cyclopropyl-2,2,2-trifluoroethyl]-1-(2,6-dichloro-4-fluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 460 mg (1.18 mmol) of the compound from Example 130Bwere reacted with 313 mg (1.76 mmol) of(1S)-1-cyclopropyl-2,2,2-trifluoroethanamine hydrochloride in thepresence of 447 mg (1.18 mmol) of HATU and 491 μl (2.82 mmol) ofN,N-diisopropylethylamine in 12 ml of dimethylformamide. The reactionwas ended by adding 40 ml of water and 60 ml of ethyl acetate, and thephases were separated. The aqueous phase was extracted three times with20 ml of ethyl acetate, and the combined organic phases were washed with40 ml of a mixture (1:1, v/v) of saturated aqueous sodium chloridesolution and aqueous 1N hydrochloric acid. The organic phase was washedthree times with 30 ml of saturated aqueous sodium chloride solution,dried over sodium sulphate and filtered, and the solvent was removedunder reduced pressure. The residue was purified by means of normalphase chromatography (cyclohexane-ethyl acetate gradient), and 369 mg(61% of theory; 99% purity) of the title compound were obtained.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=10.6 (d, 1H), 9.09 (s, 1H), 8.79 (d,1H), 7.92 (d, 2H), 7.80 (d, 1H), 4.44-4.31 (m, 1H), 1.30-1.20 (m, 1H),0.73-0.52 (m, 3H), 0.39-0.30 (m, 1H).

LC-MS (Method 1): R_(t)=1.29 min; MS (ESIpos) m/z 464 [M+H]⁺.

Example 131A7-Chloro-1-(2,6-dichloro-4-fluorophenyl)-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 1.00 g (2.58 mmol) of the compound from Example 130Bwere reacted with 633 mg (3.87 mmol) of(2R)-1,1,1-trifluorobutan-2-amine hydrochloride in the presence of 981mg (2.58 mmol) of HATU and 1.08 ml (6.19 mmol) ofN,N-diisopropylethylamine in 26 ml of dimethylformamide. The reactionwas ended by adding 40 ml of water and 60 ml of ethyl acetate, and thephases were separated. The aqueous phase was extracted three times with20 ml of ethyl acetate, and the combined organic phases were washed with40 ml of a mixture (1:1, v/v) of saturated aqueous sodium chloridesolution and aqueous 1N hydrochloric acid. The organic phase was washedthree times with 30 ml of saturated aqueous sodium chloride solution,dried over sodium sulphate and filtered, and the solvent was removedunder reduced pressure. The residue was purified by means of normalphase chromatography (cyclohexane-ethyl acetate gradient), and 1.07 g(83% of theory; 99% purity) of the title compound were obtained.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=9.90 (d, 1H), 9.10 (s, 1H), 8.78 (d,1H), 7.92 (d, 2H), 7.79 (d, 1H), 4.84-4.71 (m, 1H), 1.96-1.84 (m, 1H),1.75-1.62 (m, 1H), 0.98 (t, 3H).

LC-MS (Method 1): R_(t)=1.28 min; MS (ESIpos) m/z 496 [M+H]⁺.

Example 132A7-Chloro-1-(2,6-dichloro-4-fluorophenyl)-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 900 mg (2.30 mmol) of the compound from Example 130Bwere reacted with 438 mg (3.45 mmol) of(2S)-1,1,1-trifluorobutan-2-amine in the presence of 874 mg (2.30 mmol)of HATU and 561 μl (3.22 mmol) of N,N-diisopropylethylamine in 23 ml ofdimethylformamide. The reaction was ended by adding 40 ml of water and60 ml of ethyl acetate, and the phases were separated. The aqueous phasewas extracted three times with 20 ml of ethyl acetate, and the combinedorganic phases were washed with 40 ml of a mixture (1:1, v/v) ofsaturated aqueous sodium chloride solution and aqueous 1N hydrochloricacid. The organic phase was washed three times with 30 ml of saturatedaqueous sodium chloride solution, dried over sodium sulphate andfiltered, and the solvent was removed under reduced pressure. Theresidue was purified by means of normal phase chromatography(cyclohexane-ethyl acetate gradient), and 425 mg (37% of theory; 99%purity) of the title compound were obtained.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=9.90 (d, 1H), 9.10 (s, 1H), 8.79 (d,1H), 7.92 (d, 2H), 7.80 (d, 1H), 4.84-4.72 (m, 1H), 1.96-1.84 (m, 1H),1.76-1.62 (m, 1H), 0.99 (t, 3H).

LC-MS (Method 1): R_(t)=1.28 min; MS (ESIpos) m/z 496 [M+H]⁺.

Example 133A1-(2-Chloro-4,6-difluorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl)]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid

According to GP2, 1.40 g (3.77 mmol) of the compound from Example 108Bwere reacted with 458 mg (4.53 mmol) of (4S)-4-hydroxypyrrolidin-2-onein the presence of 782 mg (5.66 mmol) of potassium carbonate, 169 mg(754 μmol) of palladium(II) acetate and 437 mg (754 μmol) of Xantphos in26.8 ml of 1,4-dioxane at 80° C. for 1.5 h. The mixture was cooled downand extracted by stirring in a mixture of ice-water, hydrochloric acidand ethyl acetate. The mixture was filtered with suction throughkieselguhr, and the organic phase was washed with water and saturatedaqueous sodium chloride solution, dried and finally concentrated. 152 mgof the residue were purified by means of preparative HPLC (column:Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.1% formicacid gradient; 0 to 5 min. 10% acetonitrile, over 14 min. 90%acetonitrile and a further 4 min. 90% acetonitrile), and 84.2 mg (5% oftheory, 99% purity) of the title compound were obtained. The majority ofthe residue was extracted with tert-butyl methyl ether in a Soxhletapparatus for 22 h and concentrated by rotary evaporation. The residuewas stirred with 3 ml of acetonitrile, and the precipitate was filteredoff with suction, washed three times with 0.5 ml of acetonitrile anddried under high vacuum. 1.01 g (51% of theory, 83% purity) of the titlecompound were obtained.

LC-MS (Method 1): R_(t)=0.76 min; MS (ESIpos) m/z 436 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=14.41 (s, 1H), 9.24 (s, 1H), 8.77 (d,1H), 8.60 (d, 1H), 7.84-7.74 (m, 2H), 5.35 (d, 1H), 4.32-4.26 (m, 1H),3.70-3.61 (m, 1H), 3.47-3.38 (m, 1H), 2.95 (dd, 1H), 2.38 (d, 1H).

Example 134A1-(2-Chloro-4,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid

To a solution of 150 mg (404 μmol) of the compound from Example 108B in4 ml of dimethylformamide were added, at room temperature, 69.8 mg (485μmol) of (3R,4R)-pyrrolidine-3,4-diol hydrochloride and 246 μl (1.42mmol) of N,N-diisopropylethylamine. On completion of conversion, themixture was acidified to pH 1 with 1N aqueous hydrochloric acid,concentrated and purified by means of preparative HPLC (column:Chromatorex C18, 10 μm, 125×30 mm, eluent: acetonitrile/0.05% formicacid gradient; 0 to 3 min 10% acetonitrile to 15 min 90% acetonitrileand for a further 3 min 90% acetonitrile). 161 mg (90% of theory, 99%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.21 min; MS (ESIpos) m/z 438 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=15.23 (br. s, 1H), 8.98 (s, 1H), 8.31(d, 1H), 7.78-7.67 (m, 2H), 6.86 (d, 1H), 5.28-5.23 (m, 1H), 5.20-5.15(m, 1H), 4.05 (br. s, 1H), 3.93 (br. s, 1H), 3.64 (dd, 1H), 3.37 (d,1H), 3.27-3.18 (m, 1H), 3.08-2.98 (m, 1H).

Example 135A7-Chloro-N-[(1R)-1-cyclopropyl-2,2,2-trifluoroethyl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 500 mg (1.40 mmol) of the compound from Example 100Bwere reacted with 368 mg (2.09 mmol) of(1R)-1-cyclopropyl-2,2,2-trifluoroethanamine hydrochloride in thepresence of 531 mg (1.40 mmol) of HATU and 583 μl (3.35 mmol) ofN,N-diisopropylethylamine in 14 ml of dimethylformamide. The reactionwas ended by adding 20 ml of water and 30 ml of ethyl acetate, and thephases were separated. The aqueous phase was extracted three times with20 ml of ethyl acetate, and the combined organic phases were washed with20 ml of a mixture (1:1, v/v) of saturated aqueous sodium chloridesolution and aqueous 1N hydrochloric acid. The organic phase was washedthree times with 15 ml of saturated aqueous sodium chloride solution,dried over sodium sulphate and filtered, and the solvent was removedunder reduced pressure. The residue was taken up in 10 ml ofdichloromethane and purified by means of normal phase chromatography(cyclohexane-ethyl acetate gradient), and 510 mg (76% of theory; 99%purity) of the title compound were obtained.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=10.04 (d, 1H), 9.13 (s, 1H), 8.76 (d,1H), 7.79 (d, 1H), 7.66-7.58 (m, 2H), 4.43-4.35 (m, 1H), 1.29-1.19 (m,1H), 0.71-0.52 (m, 3H), 0.37-0.31 (m, 1H).

LC-MS (Method 1): R_(t)=1.23 min; MS (ESIpos) m/z 476 [M+H]⁺.

Example 136A7-Chloro-1-(2-chloro-4,6-difluorophenyl)-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 1.00 g (2.69 mmol) of the compound from Example 108Bwere reacted with 661 mg (4.04 mmol) of(2R)-1,1,1-trifluorobutan-2-amine hydrochloride in the presence of 1.02g (2.69 mmol) of HATU and 1.13 ml (6.47 mmol) ofN,N-diisopropylethylamine in 27 ml of dimethylformamide. The reactionwas ended by adding 40 ml of water and 60 ml of ethyl acetate, and thephases were separated. The aqueous phase was extracted three times with20 ml of ethyl acetate, and the combined organic phases were washed with40 ml of a mixture (1:1, v/v) of saturated aqueous sodium chloridesolution and aqueous 1N hydrochloric acid. The organic phase was washedthree times with 30 ml of saturated aqueous sodium chloride solution,dried over magnesium sulphate and filtered, and the solvent was removedunder reduced pressure. The residue was taken up in dichloromethane andpurified by means of normal phase chromatography (cyclohexane-ethylacetate gradient), and 1.01 g (78% of theory; 100% purity) of the titlecompound were obtained.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=9.92-9.85 (m, 1H), 9.13-9.08 (m, 1H),8.80-8.74 (m, 1H), 7.83-7.72 (m, 3H), 4.83-4.72 (m, 1H), 1.95-1.85 (m,1H), 1.75-1.63 (m, 1H), 1.02-0.94 (m, 3H).

LC-MS (Method 3): R_(t)=2.40 min; MS (ESIpos) m/z 480 [M+H]⁺.

Example 137A7-Chloro-4-oxo-N-[1-(trifluoromethoxy)butan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Racemate)

According to GP1, 200 mg (564 μmol) of the compound from Example 100Bwere reacted with 120 mg (620 μmol) of 1-(trifluoromethoxy)butan-2-aminehydrochloride in the presence of 241 mg (564 μmol) of HATU and 236 μl(1.35 mmol) of N,N-diisopropylethylamine in 5.7 ml of dimethylformamide.The reaction was ended by adding 10 ml of water and 15 ml of ethylacetate, and the phases were separated. The aqueous phase was extractedthree times with 20 ml of ethyl acetate, and the combined organic phaseswere washed with 40 ml of a mixture (1:1, v/v) of saturated aqueoussodium chloride solution and aqueous 1N hydrochloric acid. The organicphase was washed three times with 30 ml of saturated aqueous sodiumchloride solution, dried over magnesium sulphate and filtered, and thesolvent was removed under reduced pressure. The residue was taken up indichloromethane and purified by means of normal phase chromatography(cyclohexane-ethyl acetate gradient), and 188 mg (67% of theory; 99%purity) of the title compound were obtained.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=9.60 (d, 1H), 9.06 (s, 1H), 8.75 (d,1H), 7.76 (d, 1H), 7.66-7.57 (m, 2H), 4.28-4.14 (m, 3H), 1.76-1.53 (m,2H), 0.95 (t, 3H).

LC-MS (Method 1): R_(t)=1.23 min; MS (ESIpos) m/z 494 [M+H]⁺.

Example 138A7-Chloro-1-(2-chloro-4,6-difluorophenyl)-N-[(1R)-1-cyclopropyl-2,2,2-trifluoroethyl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 640 mg (1.72 mmol) of the compound from Example 108Bwere reacted with 459 mg (2.59 mmol) of(1R)-1-cyclopropyl-2,2,2-trifluoroethanamine hydrochloride in thepresence of 656 mg (1.72 mmol) of HATU and 721 μl (4.14 mmol) ofN,N-diisopropylethylamine in 17.3 ml of dimethylformamide. The reactionwas ended by adding 40 ml of water and 60 ml of ethyl acetate, and thephases were separated. The aqueous phase was extracted three times with20 ml of ethyl acetate, and the combined organic phases were washed with40 ml of a mixture (1:1, v/v) of saturated aqueous sodium chloridesolution and aqueous 1N hydrochloric acid. The organic phase was washedthree times with 30 ml of saturated aqueous sodium chloride solution,dried over magnesium sulphate and filtered, and the solvent was removedunder reduced pressure. The residue was taken up in dichloromethane andpurified by means of normal phase chromatography (cyclohexane-ethylacetate gradient), and 635 mg (75% of theory; 100% purity) of the titlecompound were obtained.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=10.04 (d, 1H), 9.11 (s, 1H), 8.77 (d,1H), 7.82-7.71 (m, 3H), 4.46-4.32 (m, 1H), 1.29-1.19 (m, 1H), 0.73-0.52(m, 3H), 0.39-0.29 (m, 1H).

LC-MS (Method 3): R_(t)=2.41 min; 492 [M+H]⁺.

Example 139A(5R)-5-({[tert-Butyl(dimethyl)silyl]oxy}methyl)pyrrolidin-2-one

To a solution of 1.03 g (8.95 mmol) of(5R)-5-(hydroxymethyl)pyrrolidin-2-one and 914 mg (13.4 mmol) ofimidazole in 20 ml of dimethylformamide were added, at 0° C., 1.39 g(8.95 mmol) of tert-butyldimethylsilyl chloride. The mixture was stirredat 0° C. for 30 min and at room temperature overnight. Subsequently, allvolatile constituents were removed under reduced pressure and theresidue was admixed with 100 ml of water and extracted three times with30 ml of ethyl acetate. The combined organic phases were washed with 30ml of saturated aqueous sodium chloride solution, dried over magnesiumsulphate and filtered, and the solvent was removed under reducedpressure. 1.56 g (76% of theory, 100% purity) of the title compound wereobtained.

¹H NMR (400 MHz, CDCl₃) δ [ppm]=5.70 (br. s, 1H), 3.79-3.72 (m, 1H),3.63 (dd, 1H), 3.44 (dd, 1H), 2.38-2.31 (m, 2H), 2.23-2.12 (m, 1H),1.78-1.67 (m, 1H), 0.89 (s, 9H), 0.06 (s, 6H).

LC-MS (Method 1): R_(t)=0.97 min; 230 [M+H]⁺.

Example 140A N-(Cyclopropylmethylene)-2-methylpropane-2-(R)-sulphinamide

To a solution of 1.73 g (14.3 mmol) of(R)-2-methylpropane-2-sulphinamide and 2.00 g (28.5 mmol) ofcyclopropanecarbaldehyde in 85.6 ml of dichloromethane were added 6.83 g(42.8 mmol) of copper(II) sulphate (dry). The mixture was stirred atroom temperature for a further 18 h and then filtered through 3 cm ofCelite and washed through with dichloromethane. The organic phase waswashed twice with 10 ml of a 10% aqueous ammonium chloride solution,dried over sodium sulphate and filtered, and the solvent was removedunder reduced pressure. 2.47 g (86% of theory, 86% purity) of the titlecompound were obtained.

LC-MS (Method 3): R_(t)=1.37 min; 174 [M+H]⁺.

Example 140BN-[(1S)-1-Cyclopropyl-2,2-difluoro-2-(phenylsulphonyl)ethyl]-2-methylpropane-2-(R)-sulphinamide

To a solution of 728 mg (4.20 mmol) of the compound from Example 140Aand 769 mg (4.00 mmol) of difluoromethyl phenyl sulphone were added, at−78° C., 4.8 ml (4.8 mmol, 1 M in THF) of lithium hexamethyldisilazide,and the mixture was stirred for a further 20 min. The reaction was endedby adding 20 ml of saturated aqueous sodium chloride solution and themixture was extracted three times with 50 ml of ethyl acetate. Thecombined organic phases were dried over sodium sulphate, filtered andconcentrated by rotary evaporation. The residue was dissolved in 4 ml ofdichloromethane and purified by means of normal phase chromatography(cyclohexane-ethyl acetate gradient). Recovered reactant from compound140A was converted once again in an analogous manner and the productfractions were combined. 897 mg (58%) of the title compound wereobtained.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=7.98-7.88 (m, 3H), 7.79-7.73 (m, 2H),5.80 (d, 1H), 3.43-3.33 (m, 1H), 1.33-1.22 (m, 1H), 0.77-0.48 (m, 4H).

LC-MS (Method 1): R_(t)=0.93 min; MS (ESIpos) m/z 366 [M+H]⁺.

Example 140CN-[(1S)-1-Cyclopropyl-2,2-difluoroethyl]-2-methylpropane-2-(R)-sulphinamide

To a suspension of 650 mg (1.78 mmol) of the compound from Example 140Band 1.79 g (12.6 mmol) of sodium hydrogenphosphate in 23 ml of methanolwere added, at −20° C., 4.02 g of sodium amalgam (5% sodium). Themixture was stirred for a further 4.5 h, the liquid was decanted off andall volatile constituents were removed under reduced pressure. 15 ml ofsaturated aqueous sodium chloride solution were added and the mixturewas extracted three times with 15 ml of ethyl acetate. The combinedorganic phases were dried over sodium sulphate and filtered, and thesolvent was removed under reduced pressure. 397 mg (98% of theory, 99%purity) of the title compound were obtained.

LC-MS (Method 1): R_(t)=0.79 min; MS (ESIpos) m/z 226 [M+H]⁺.

Example 140D (1S)-1-Cyclopropyl-2,2-difluoroethanamine hydrochloride

To a solution of 396 mg (1.76 mmol) of the compound from Example 140C in24.8 ml of methanol were added 6.20 ml (24.8 mmol, 4N in dioxane) ofhydrochloric acid, and the mixture was stirred for a further 30 min.Subsequently, the mixture was concentrated to dryness by rotaryevaporation and stirred with 8 ml of diethyl ether, centrifuged anddecanted, and the residue was dried under high vacuum. 209 mg (75% oftheory, 99% purity) of the title compound were obtained.

¹H NMR (400 MHz, D₂O-d₂) 6 [ppm]=6.28 (t, 1H), 3.03-2.93 (m, 1H),1.13-1.04 (m, 1H), 0.84-0.76 (m, 2H), 0.62-0.46 (m, 2H).

Optical rotation: MeOH, conc. 0.4850 g/100 ml, λ: 365 nm [−15.12°]

Example 141A tert-Butyl[(2R)-1-{[6-{[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]carbamoyl}-5-oxo-8-(2,4,6-trifluorophenyl)-5,8-dihydro-1,8-naphthyridin-2-yl]amino}propan-2-yl]carbamate

To a solution of 150 mg (315 μmol) of the compound from Example 126A in3.1 ml of dimethylformamide were added, at room temperature, 93.0 mg(441 μmol) of tert-butyl [(2R)-1-aminopropan-2-yl]carbamatehydrochloride and 225 μl (1.29 mmol) of N,N-diisopropylethylamine. Themixture was stirred for a further 72 h. The reaction solution wasdiluted with 1 ml of acetonitrile and 0.5 ml of water and separated bymeans of preparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm,solvent: acetonitrile/0.1% formic acid gradient; 0 to 5 min 10%acetonitrile, over 14 min to 90% acetonitrile and for a further 4 min90% acetonitrile). 161 mg (83% of theory, 99% purity) of the titlecompound were obtained.

LC-MS (Method 3): R_(t)=2.24 min; MS (ESIpos) m/z 614 [M+H]⁺.

Example 141B7-{[(2R)-2-Aminopropyl]amino}-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamidetrifluoroacetic acid

To a solution of 166 mg (271 μmol) of the compound from Example 141A in10 ml of dichloromethane were added 5.00 ml (64.9 mmol) oftrifluoroacetic acid while cooling with an ice bath. The mixture wasstirred at room temperature for a further 2 h and then all volatilecomponents were removed under reduced pressure. The residue wascodistilled with toluene and dried under high vacuum. 170 mg (99% oftheory, 99% purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.32 min; MS (ESIpos) m/z 514 [M+H]⁺.

Example 142AN-[(15)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-{[(2S)-2-hydroxypropyl]amino}-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

To a solution of 150 mg (315 μmol) of the compound from Example 126A in3.1 ml of dimethylformamide were added, at room temperature, 33.2 mg(441 μmol) of (2S)-1-aminopropan-2-ol and 192 μl (1.10 mmol) ofN,N-diisopropylethylamine. The mixture was stirred for a further 48 h.The reaction solution was diluted with 1 ml of acetonitrile, 0.5 ml ofwater and 0.1 ml of 1N aqueous hydrochloric acid and separated by meansof preparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm, solvent:acetonitrile/0.1% formic acid gradient; 0 to 5 min 10% acetonitrile,over 14 min to 90% acetonitrile and for a further 4 min 90%acetonitrile). 136 mg (83% of theory, 99% purity) of the title compoundwere obtained.

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]=10.60 (d, 1H), 8.77 (s, 1H), 8.21-8.11(m, 2H), 7.60-7.51 (m, 2H), 6.74 (d, 1H), 4.65 (d, 1H), 4.44-4.32 (m,1H), 3.62-3.50 (m, 1H), 3.06-2.96 (m, 1H), 2.84-2.75 (m, 1H), 1.25-1.15(m, 1H), 0.83 (d, 3H), 0.69-0.47 (m, 3H), 0.38-0.30 (m, 1H).

LC-MS (Method 3): R_(t)=1.88 min; MS (ESIpos) m/z 515 [M+H]⁺.

Example 143A tert-Butyl[(2S)-1-{[6-{[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]carbamoyl}-5-oxo-8-(2,4,6-trifluorophenyl)-5,8-dihydro-1,8-naphthyridin-2-yl]amino}propan-2-yl]carbamate

To a solution of 150 mg (315 μmol) of the compound from Example 126A in3.1 ml of dimethylformamide were added, at room temperature, 93.0 mg(441 μmol) of tert-butyl [(2S)-1-aminopropan-2-yl]carbamatehydrochloride and 225 μl (1.29 mmol) of N,N-diisopropylethylamine. Themixture was stirred for a further 72 h. The reaction solution wasdiluted with 0.2 ml of acetonitrile and 0.5 ml of water and separated bymeans of preparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm,solvent: acetonitrile/0.1% formic acid gradient; 0 to 5 min 10%acetonitrile, over 14 min to 90% acetonitrile and for a further 4 min90% acetonitrile). 174 mg (89% of theory, 99% purity) of the titlecompound were obtained.

LC-MS (Method 3): R_(t)=2.22 min; MS (ESIpos) m/z 614 [M+H]⁺.

Example 143B7-{[(2S)-2-Aminopropyl]amino}-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamidetrifluoroacetic acid

To a solution of 174 mg (283 μmol) of the compound from Example 143A in10 ml of dichloromethane were added 436 μl (5.66 mmol) oftrifluoroacetic acid while cooling with an ice bath. The mixture wasstirred at room temperature for 3 h and then a further 10 equivalents oftrifluoroacetic acid were added and the mixture was stirred at roomtemperature for a further hour. All volatile components were removedunder reduced pressure, and the residue was codistilled twice with 20 mlof toluene and dried under high vacuum. 185 mg (quantitative, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.29 min; MS (ESIpos) m/z 514 [M+H]⁺.

Example 144A tert-Butyl[1-({[6-{[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]carbamoyl}-5-oxo-8-(2,4,6-trifluorophenyl)-5,8-dihydro-1,8-naphthyridin-2-yl]amino}methyl)cyclopropyl]carbamate

To a solution of 150 mg (315 μmol) of the compound from Example 126A in3.1 ml of dimethylformamide were added, at room temperature, 98.3 mg(441 μmol) of tert-butyl [1-(aminomethyl)cyclopropyl]carbamatehydrochloride and 225 μl (1.29 mmol) of N,N-diisopropylethylamine. Themixture was stirred for a further 48 h. The reaction solution wasdiluted with 0.2 ml of acetonitrile and 0.5 ml of water and separated bymeans of preparative HPLC (column: Chromatorex C18, 10 m, 125×30 mm,solvent: acetonitrile/0.05% formic acid gradient; 0 to 3 min 10%acetonitrile, to 35 min 90% acetonitrile and for a further 3 min 90%acetonitrile). 171 mg (86% of theory, 99% purity) of the title compoundwere obtained.

LC-MS (Method 3): R_(t)=2.30 min; MS (ESIpos) m/z 626 [M+H]⁺.

Example 144B7-{[(1-Aminocyclopropyl)methyl]amino}-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamidebis(trifluoroacetate)

To a solution of 170 mg (272 μmol) of the compound from Example 144A in7.9 ml of dichloromethane were added 419 μl (5.44 mmol) oftrifluoroacetic acid while cooling with an ice bath. The mixture wasstirred at room temperature for a further 2.5 h. All volatile componentswere removed under reduced pressure, and the residue was codistilledwith toluene and finally lyophilized. 185 mg (89% of theory, 99% purity)of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.31 min; MS (ESIpos) m/z 526 [M+H]⁺.

Example 145A tert-Butyl(1-{[6-{[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]carbamoyl}-5-oxo-8-(2,4,6-trifluorophenyl)-5,8-dihydro-1,8-naphthyridin-2-yl]amino}-2-methylpropan-2-yl)carbamate

To a solution of 150 mg (315 μmol) of the compound from Example 126A in3.1 ml of dimethylformamide were added, at room temperature, 99.2 mg(441 μmol) of tert-butyl (1-amino-2-methylpropan-2-yl)carbamatehydrochloride and 225 μl (1.29 mmol) of N,N-diisopropylethylamine. Themixture was stirred for a further 48 h. The reaction solution wasdiluted with 0.2 ml of acetonitrile and 0.5 ml of water and separated bymeans of preparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm,solvent: acetonitrile/0.1% formic acid gradient; 0 to 5 min 10%acetonitrile, over 14 min to 90% acetonitrile and for a further 4 min90% acetonitrile). 174 mg (87% of theory, 99% purity) of the titlecompound were obtained.

LC-MS (Method 3): R_(t)=2.40 min; MS (ESIpos) m/z 628 [M+H]⁺.

Example 145B 7-[(2-Amino-2-methylpropyl)amino]-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamidebis(trifluoroacetate)

To a solution of 172 mg (274 μmol) of the compound from Example 145A in7.9 ml of dichloromethane were added 422 μl (5.48 mmol) oftrifluoroacetic acid while cooling with an ice bath. The mixture wasstirred at room temperature for a further 2.5 h. All volatile componentswere removed under reduced pressure, and the residue was codistilledwith toluene and finally lyophilized. 185 mg (91% of theory, 99% purity)of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.33 min; MS (ESIpos) m/z 528 [M+H]⁺.

Example 146A Ethyl7-({(2R)-2-[(tert-butoxycarbonyl)amino]propyl}amino)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylate

To a solution of 1.50 g (3.92 mmol) of the compound from Example 100A in25 ml of dimethylformamide were added, at room temperature, 991 mg (4.70mmol) of tert-butyl [(2R)-1-aminopropan-2-yl]carbamate hydrochloride and2.39 ml (13.7 mmol) of N,N-diisopropylethylamine. The mixture wasstirred at room temperature for 12 h and at 60° C. for 37 h. Thereaction solution was added to 250 ml of water and adjusted to pH 5 with1N aqueous hydrochloric acid. The precipitate was filtered off withsuction, washed with water and dried under high vacuum. 1.81 g (85% oftheory, 95% purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.82 min; MS (ESIpos) m/z 521 [M+H]⁺.

Example 146B Ethyl7-{[(2R)-2-aminopropyl]amino}-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylatetrifluoroacetate

To a solution of 1.80 g (3.46 mmol) of the compound from Example 146A in100 ml of dichloromethane were added 5.33 ml (69.2 mmol) oftrifluoroacetic acid while cooling with an ice bath. The mixture wasstirred at room temperature for a further 2.5 h. All volatile componentswere removed under reduced pressure, and the residue was codistilledwith toluene and finally lyophilized. 2.50 g (quantitative, 99% purity)of the title compound were obtained.

LC-MS (Method 3): R_(t)=0.92 min; MS (ESIpos) m/z 421 [M+H]⁺.

Example 146C Ethyl7-[(4R)-4-methyl-2-oxoimidazolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylate

To a solution of 2.50 g (4.68 mmol) of the compound from Example 146B in103 ml of dimethylformamide were added, at room temperature, 647 mg(4.68 mmol) of potassium carbonate and 1.89 g (11.7 mmol) of1,1′-carbonyldiimidazole. The mixture was stirred for a further 6 h.Subsequently, the reaction solution was added to 600 ml of water, 5 mlof 1N aqueous hydrochloric acid were added, and the precipitate wasfiltered off with suction, washed with water and dried under highvacuum. 1.20 g (57% of theory, 99% purity) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=0.86 min; MS (ESIpos) m/z 447 [M+H]⁺.

Example 146D7-[(4R)-4-Methyl-2-oxoimidazolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid

To an initial charge of 1.19 g (2.67 mmol) of the compound from Example146C in 8 ml of water were added 8 ml of 36 percent aqueous hydrochloricacid and 8 ml of THF, and the mixture was stirred at 110° C. for 4 h.The reaction mixture was cooled to RT and diluted with 100 ml of water.The precipitate was filtered off with suction, washed with water anddried under high vacuum. 995 mg (87% of theory, 97% purity) of the titlecompound were obtained.

LC-MS (Method 3): R_(t)=1.49 min; MS (ESIpos): m/z=419 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6): δ [ppm]=14.65 (s, 1H), 9.19 (s, 1H), 8.60 (d,1H), 8.50 (d, 1H), 7.91 (s, 1H), 7.65-7.55 (m, 2H), 3.81-3.70 (m, 2H),3.14-3.06 (m, 1H), 1.13 (d, 3H).

Example 147A N-Benzyl-1,1,1,2,2-pentafluorobutan-3-amine (Racemate)

To a solution of 2.00 g (12.2 mmol) of 3,3,4,4,4-pentafluorobutan-2-onein 10 ml of dichloromethane were added, at 0° C., 5.40 ml (18.3 mmol) oftitanium tetraisopropoxide and 2.66 ml (24.4 mmol) of benzylamine. Themixture was stirred at RT for a further 90 min before being cooled downagain to 0° C. Subsequently, 2.14 g (34.1 mmol) of sodiumcyanoborohydride, 36 ml of methanol and 3 A molecular sieve were added.The mixture was warmed to RT and stirred for a further 2 d. The reactionsolution was admixed with a little water and ethyl acetate and filtered.The filtrate was washed twice with saturated aqueous sodiumhydrogencarbonate solution and once with saturated aqueous sodiumchloride solution. The organic phase was dried over sodium sulphate andfiltered, and the solvent was removed under reduced pressure. Theresidue was purified twice by means of normal phase chromatography(ethyl acetate/cyclohexane 1/20), and 1.65 g (48% of theory; 91% purity)of the title compound were obtained.

LC-MS (Method 6): R_(t)=2.17 min; MS (ESIpos): m/z=254 [M+H]⁺.

¹H NMR (500 MHz, DMSO-d6): δ [ppm]=7.28-7.36 (m, 4H), 7.20-7.27 (m, 1H),3.83 (dd, 1H), 3.72 (dd, 1H), 3.22-3.30 (m, 1H), 2.43-2.48 (m, 1H), 1.20(d, 3H).

Example 147B 1,1,1,2,2-Pentafluorobutan-3-amine hydrochloride (Racemate)

To a solution of 1.50 g (5.92 mmol) ofN-benzyl-1,1,1,2,2-pentafluoropentan-3-amine in 27.4 ml of methanol wereadded 150 mg of palladium on charcoal (10%), and hydrogenation waseffected at standard pressure and room temperature for 6 h. The reactionmixture was then filtered through a Millipore filter and the solvent wasremoved under reduced pressure. The receiver containing the solventdistilled off was then transferred to a flask and admixed with 4 Naqueous hydrochloric acid in dioxane and concentrated again. The residuewas stirred with diethyl ether and the precipitate was filtered off withsuction and dried under high vacuum. 456 mg (39% of theory, 100% purity)of the title compound were obtained.

¹H NMR (500 MHz, DMSO-d6): δ [ppm]=9.21 (br. s, 3H), 4.40-4.29 (m, 1H),1.41 (d, 3H).

Example 148A 3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)pyrrolidin-2-one(Racemate)

To a solution of 110 mg (955 μmol) of 3-(hydroxymethyl)pyrrolidin-2-oneand 97.6 mg (1.43 mmol) of imidazole in 5 ml of dimethylformamide wereadded, at 0° C., 148 mg (955 μmol) of tert-butyldimethylsilyl chloride.The mixture was stirred at 0° C. for 30 min and at room temperatureovernight. Subsequently, all volatile constituents were removed underreduced pressure and the residue was admixed with 10 ml of water andextracted three times with 20 ml of ethyl acetate. The combined organicphases were washed with 30 ml of saturated aqueous sodium chloridesolution, dried over magnesium sulphate and filtered, and the solventwas removed under reduced pressure. 115 mg (52% of theory, 100% purity)of the title compound were obtained.

¹H NMR (400 MHz, CDCl₃) δ [ppm]=5.44 (br. s, 1H), 3.84 (dd, 1H), 3.75(dd, 1H), 3.35-3.22 (m, 2H), 2.48-2.40 (m, 1H), 2.26-2.06 (m, 2H), 0.82(s, 9H), 0.00 (d, 6H).

LC-MS (Method 3): R_(t)=1.81 min; MS (ESIpos) m/z 230 [M+H]⁺.

Example 149A7-[(3R)-3-Hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid

According to GP2, 270 mg (761 μmol) of the compound from Example 100Bwere reacted with 92.4 mg (914 μmol) of (3R)-3-hydroxypyrrolidin-2-onein the presence of 158 mg (1.14 mmol) of potassium carbonate, 17 mg (76μmol) of palladium(II) acetate and 88.1 mg (152 μmol) of Xantphos in 6ml of 1,4-dioxane at 80° C. for 12 h. Catalyst was added to the mixtureonce again, and the mixture was stirred at 80° C. for a further 5 h.Subsequently, the reaction mixture was extracted by stirring in amixture of ice-water, hydrochloric acid and ethyl acetate. The mixturewas filtered with suction through kieselguhr, and the organic phase waswashed with water and saturated aqueous sodium chloride solution, driedover sodium sulphate, filtered and concentrated. The residue wasdissolved in 6.5 ml of acetonitrile and 0.5 ml of water and purified bymeans of preparative HPLC (column: Chromatorex C18, 10 m, 125×30 mm,solvent: acetonitrile/0.1% formic acid gradient; 0 to 5 min 10%acetonitrile, over 14 min to 90% acetonitrile and for a further 4 min90% acetonitrile). 159 mg (49% of theory, 99% purity) of the titlecompound were obtained.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=14.37 (br. s, 1H), 9.25 (s, 1H), 8.77(d, 1H), 8.60 (d, 1H), 7.66-7.56 (m, 2H), 5.93 (d, 1H), 4.45-4.36 (m,1H), 3.62-3.53 (m, 1H), 2.38-2.26 (m, 1H), 1.85-1.71 (m, 1H), oneresonance partially under the water signal.

LC-MS (Method 1): R_(t)=0.73 min; MS (ESIpos) m/z 420 [M+H]⁺.

Example 151A tert-Butyl (5-oxopyrrolidin-3-yl)carbamate (Racemate)

To a solution of 100 mg (732 μmol) of 4-aminopyrrolidin-2-onehydrochloride (racemate) in 1.5 ml of water and 3.5 ml of dioxane wereadded, at room temperature, 185 mg (2.19 mmol) of sodiumhydrogencarbonate and 168 mg (769 μmol) of di-tert-butyl dicarbonate.The mixture was stirred overnight. The mixture was then admixed withwater and extracted three times with ethyl acetate. The combined organicphases were dried over magnesium sulphate and concentrated, and theresidue was dried under high vacuum. 69.2 mg (47% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 1): R_(t)=0.48 min; MS (ESIpos): m/z=201 [M+H]⁺

Example 151B tert-Butyl{5-oxo-1-[5-oxo-6-{[(2S)-1,1,1-trifluorobutan-2-yl]carbamoyl}-8-(2,4,6-trifluorophenyl)-5,8-dihydro-1,8-naphthyridin-2-yl]pyrrolidin-3-yl}carbamate(Diastereomer Mixture)

Potassium carbonate (17.9 mg, 129 μmol), palladium(II) acetate (3.87 mg,17.2 μmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (9.98 mg,17.2 μmol) were stirred in 4.0 ml of dioxane under argon at RT for 10minutes. Then the compound from Example 115A (40.0 mg, 86.2 μmol) andthe compound from Example 151A (20.7 mg, 103 μmol) were added and themixture was stirred at 80° C. for 4 h. The mixture was purified directlyby preparative RP-HPLC (column: Reprosil 125×30; 10p, flow rate: 50ml/min, MeCN/water, 0.1% TFA). The volatile constituents were removedunder reduced pressure and the residue was dried under high vacuum. Thisgave 30.7 mg (79% pure, 45% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.20 min; MS (ESIpos): m/z=628 [M+H]⁺.

Example 151C7-[4-Amino-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(bis)trifluoroacetate (Diastereomer Mixture)

The compound from Example 151B (30.7 mg, 79% purity, 38.5 μmol) wasdissolved in 2.0 ml of dichloromethane, trifluoroacetic acid (150 μl,1.9 mmol) was added, and the mixture was stirred at RT for 5 h. Thevolatile constituents were removed under reduced pressure and theresidue was purified by means of preparative RP-HPLC (column: Reprosil125×30; 10p, flow rate: 50 ml/min, MeCN/water/0.1% TFA). The volatileconstituents were removed under reduced pressure and the residue wasdried under high vacuum. This gave 25.7 mg (95% purity, 84% of theory)of the title compound.

LC-MS (Method 1): R_(t)=0.72 min; MS (ESIpos): m/z=528 [M+H]⁺

Example 152A N-[(5-Oxopyrrolidin-3-yl)methyl]acetamide (Racemate)

To an initial charge of 4-(aminomethyl)pyrrolidin-2-one hydrochloride(racemate) (30.0 mg, 199 μmol) in 1.0 ml of dichloromethane was addedtriethylamine (83 μl, 600 μmol). Acetyl chloride (17 μl, 240 μmol) wasadded to the reaction mixture at 0° C., and the reaction mixture wasstirred at RT overnight. The organic phase was washed once with waterand dried over magnesium sulphate. The volatile constituents wereremoved under reduced pressure and the residue was dried under highvacuum. This gave 11.7 mg of the title compound, which was usedimmediately in the next reaction stage without further purification.

Example 153A N-Benzyl-1,1,1,2,2-pentafluoropentan-3-amine (Racemate)

To a solution of 2.00 g (11.4 mmol) of 1,1,1,2,2-pentafluoropentan-3-onein 10 ml of dichloromethane were added, at 0° C., 5.03 ml (17.0 mmol) oftitanium tetraisopropoxide and 2.48 ml (22.7 mmol) of benzylamine. Themixture was stirred at RT for a further 90 min before being cooled downagain to 0° C. Subsequently, 2.00 g (31.8 mmol) of sodiumcyanoborohydride, 36 ml of methanol and 3 A molecular sieve were added.The mixture was warmed to RT and stirred for a further 2 d. The reactionsolution was then admixed with a little water and ethyl acetate andfiltered. The filtrate was washed twice with saturated aqueous sodiumhydrogencarbonate solution and once with saturated aqueous sodiumchloride solution. The organic phase was dried over sodium sulphate andfiltered, and the solvent was removed under reduced pressure. Theresidue was purified by means of normal phase chromatography (ethylacetate/cyclohexane 1/20), and 989 mg (25% of theory; 76% purity) of thetitle compound were obtained.

LC-MS (Method 1): R_(t)=1.27 min; MS (ESIpos): m/z=268 [M+H]⁺

¹H NMR (400 MHz, DMSO-d6): δ [ppm]=7.21-7.36 (m, 5H), 3.73-3.85 (m, 2H),3.05-3.20 (m, 1H), 1.63-1.75 (m, 1H), 1.49-1.61 (m, 1H), 1.15-1.20 (m,1H), 0.96 (t, 3H).

Example 153B 1,1,1,2,2-Pentafluoropentan-3-amine hydrochloride(Racemate)

To a solution of 980 g (2.75 mmol) of the compound from Example 153A in11.3 ml of methanol were added 75 mg of palladium on charcoal (10%), andhydrogenation was effected at standard pressure and room temperature for6 h. The reaction mixture was then filtered through a Millipore filterand the solvent was removed under reduced pressure. The receivercontaining the solvent distilled off was then transferred to a flask andadmixed with 4 N aqueous hydrochloric acid in dioxane and concentratedagain. The residue was stirred with diethyl ether and the precipitatewas filtered off with suction and dried under high vacuum. 379 mg (65%of theory, 100% purity) of the title compound were obtained.

¹H NMR (400 MHz, DMSO-d6): δ [ppm]=8.97 (br. s, 3H), 4.16-4.28 (m, 1H),1.67-1.94 (m, 2H), 1.05 (t, 3H).

Example 154A7-Chloro-N-(1,1,1,3,3,3-hexafluoropropan-2-yl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

To a solution of 500 mg (1.41 mmol) of the compound from Example 100B,259 mg (1.55 mmol) of 1,1,1,3,3,3-hexafluoropropan-2-amine and 740 μl(4.20 mmol) of DIPEA in 13 ml of ethyl acetate were added dropwise 3.30ml (5.60 mmol) of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane2,4,6-trioxide (T3P, 50% in DMF). The mixture was stirred at 80° C.overnight. The reaction mixture was poured into water and ethyl acetate,and the phases were separated. The organic phase was washed three timeswith water and once with saturated aqueous sodium chloride solution,dried over sodium sulphate and filtered, and the solvent was removedunder reduced pressure. The residue was dissolved in a littleacetonitrile, filtered through a Millipore filter and purified by meansof preparative HPLC (column: Chromatorex C18, 10 μm, 125*40 mm, solvent:acetonitrile, water, 0.1% formic acid). The substance was recrystallizedfrom acetonitrile, filtered off with suction, washed with a littleacetonitrile and dried. 432 mg (61% of theory, 100% purity) of the titlecompound were obtained.

LC-MS (Method 3): R_(t)=2.39 min; MS (ESIpos): m/z=504 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.76 (d, 1H), 9.26 (s, 1H), 8.78 (d,1H), 7.81 (d, 1H), 7.59-7.66 (m, 2H), 6.36-6.47 (m, 1H).

Example 155A7-[7-Hydroxy-5-azaspiro[2.4]hept-5-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid (Racemate)

According to GP3, 500 mg (1.41 mmol) of the compound from Example 100Bwere reacted with 239 mg (1.55 mmol, 97% purity) of5-azaspiro[2.4]heptan-7-ol hydrochloride in the presence of 860 μl (4.90mmol) of DIPEA in 14 ml of DMF. The mixture was diluted with water, 1 Maqueous hydrochloric acid and ethyl acetate. The phases were separatedand the aqueous phase was extracted three times with ethyl acetate. Thecombined organic phases were washed with saturated aqueous sodiumchloride solution, dried over sodium sulphate and filtered, and thesolvent was removed under reduced pressure. The crude product waspurified by means of preparative HPLC (column: Chromatorex C18, 10 m,125*40 mm, solvent: acetonitrile, water, 0.1% formic acid), and 422 mg(63% of theory, 90% purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.60 min; MS (ESIpos): m/z=432 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=15.19 (br s, 1H), 8.99-9.04 (m, 1H),8.31 (d, 1H), 7.51-7.62 (m, 2H), 6.89 (d, 0.40H), 6.76 (d, 0.60H), 5.04(br s, 1H), 3.61-3.80 (m, 2H), 3.13-3.53 (m, 2.60H), 2.89 (d, 0.40H),0.78-0.87 (m, 1H), 0.45-0.63 (m, 3H).

Example 156A7-[(3R,4S)-3,4-Dihydroxypyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid

According to GP3, 500 mg (1.41 mmol) of the compound from Example 100Bwere reacted with 236 mg (1.69 mmol) of (3R,4S)-pyrrolidine-3,4-diolhydrochloride in the presence of 860 μl (4.90 mmol) of DIPEA in 6.3 mlof DMF. The mixture was diluted with water, 1 M aqueous hydrochloricacid and ethyl acetate. The phases were separated and the aqueous phasewas extracted three times with ethyl acetate. The combined organicphases were washed with saturated aqueous sodium chloride solution,dried over sodium sulphate and filtered, and the solvent was removedunder reduced pressure. The crude product was crystallized from ethylacetate and cyclohexane, filtered off with suction, washed with a littleethyl acetate/cyclohexane and dried. 459 mg (77% of theory) of the titlecompound were obtained.

LC-MS (Method 3): R_(t)=1.19 min; MS (ESIpos): m/z=422 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=15.21 (s, 1H), 9.02 (s, 1H), 8.29 (d,1H), 7.54-7.62 (m, 2H), 6.84 (d, 1H), 5.07 (d, 1H), 4.97 (d, 1H),4.10-4.20 (m, 1H), 4.00-4.07 (m, 1H), 3.63 (dd, 1H), 3.24 (dd, 1H), 3.01(dd, 1H).

Example 157A7-[4-(Methoxycarbonyl)piperazin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid

According to GP3, 500 mg (1.41 mmol) of the compound from Example 100Bwere reacted with 244 mg (1.69 mmol) of methyl piperazine-1-carboxylatein the presence of 860 μl (4.90 mmol) of DIPEA in 6.3 ml of DMF. Themixture was diluted with acetonitrile, a little water and formic acid.The substance was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 380 mg (58% of theory, 98%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.63 min; MS (ESIpos): m/z=463 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=15.06 (br s, 1H), 9.04 (s, 1H), 8.35(d, 1H), 7.58 (t, 2H), 7.21 (d, 1H), 3.61 (s, 3H), 3.51-3.59 (m, 4H),3.37-3.44 (m, 4H).

Example 158A Ethyl 4-{[(benzyloxy)carbonyl]amino}-3-oxobutanoate

To a solution of 15.0 g (71.7 mmol) of N-[(benzyloxy)carbonyl]glycine in534 ml of THF were added 9.24 g (57.0 mmol) of carbonyldiimidazole(CDI), and the mixture was stirred at RT for 2.5 h. Subsequently, whilecooling with an ice bath, 9.76 g (57.4 mmol) of potassium3-ethoxy-3-oxopropanoate and 4.95 g (52.0 mmol) of magnesium chloridewere added. On completion of addition, stirring was continued at 50° C.for a further 48 h. The solvent was removed under reduced pressure, theresidue was taken up with ethyl acetate and saturated aqueous ammoniumchloride solution, and the phases were separated. The organic phase waswashed with saturated aqueous sodium chloride solution, dried oversodium sulphate and filtered, and the solvent was removed under reducedpressure. The residue was purified by means of normal phasechromatography (ethyl acetate-cyclohexane gradient), and 12.7 g (60% oftheory; 95% purity) of the title compound were obtained.

LC-MS (Method 1): R_(t)=0.83 min; MS (ESIneg): m/z=278 [M−H]⁻

¹H NMR (400 MHz, DMSO-d6): δ [ppm]=7.56 (br t, 1H), 7.25-7.41 (m, 5H),5.04 (s, 2H), 4.09 (q, 2H), 3.97 (d, 2H), 3.60 (s, 2H), 1.19 (t, 3H).

Example 158B Ethyl4-{[(benzyloxy)carbonyl]amino}-2-methyl-3-oxobutanoate (Racemate)

A suspension of 1.00 g (3.58 mmol) of ethyl4-{[(benzyloxy)carbonyl]amino}-3-oxobutanoate, 669 μl (10.7 mmol) ofiodomethane and 990 mg (7.16 mmol) of potassium carbonate in 15 ml ofacetone was reacted in a microwave at 50° C. for 2 h. Microwaveirradiation was continued, while monitoring the reaction, at 45° C. fora further 2 h. The reaction mixture was poured into water and extractedthree times with ethyl acetate. The combined organic phases were washedwith saturated aqueous sodium chloride solution, dried over sodiumsulphate and filtered, and the solvent was removed under reducedpressure. The residue was dissolved in a little acetonitrile, filteredthrough a Millipore filter and separated in two runs by means ofpreparative HPLC (column: Chromatorex C18, 10 μm, 125*40 mm, solvent:acetonitrile, water, 0.1% formic acid). 536 mg (51% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 1): R_(t)=0.87 min; MS (ESIneg): m/z=292 [M−H]⁻

¹H NMR (400 MHz, DMSO-d6): δ [ppm]=7.57 (br t, 1H), 7.24-7.40 (m, 5H),5.04 (s, 2H), 4.09 (q, 2H), 4.03 (d, 2H), 3.80 (q, 1H), 1.22-1.09 (m,6H).

Example 158C Ethyl4-{[(benzyloxy)carbonyl]amino}-3-hydroxy-2-methylbutanoate (DiastereomerMixture)

To a solution of 533 mg (1.82 mmol) of ethyl4-{[(benzyloxy)carbonyl]amino}-2-methyl-3-oxobutanoate in 9.2 ml ofmethanol were added, at −78° C., 96.2 mg (2.54 mmol) of sodiumborohydride. The mixture was warmed gradually to −15° C. whilemonitoring the reaction. At −15° C., the reaction was ended by addingsaturated aqueous ammonium chloride solution. The mixture was extractedthree times with ethyl acetate. The combined organic phases were washedwith saturated aqueous sodium chloride solution, dried over sodiumsulphate and filtered, and the solvent was removed under reducedpressure. The residue was taken up in a little acetonitrile and purifiedin two runs by means of preparative HPLC (column: Chromatorex C18, 10 m,125*40 mm, solvent: acetonitrile, water, 0.1% formic acid). 398 mg (74%of theory, 100% purity) of the title compound were obtained.

LC-MS (Method 1): R_(t)=0.80 min; MS (ESIpos): m/z=296 [M+H]⁺

¹H NMR (400 MHz, DMSO-d6): δ [ppm]=7.26-7.45 (m, 5H), 7.20-7.25 (m,0.3H), 7.11 (br t, 0.7H), 5.01 (s, 2H), 4.90-4.97 (m, 1H), 3.98-4.08 (m,2H), 3.81-3.88 (m, 0.3H), 3.63-3.71 (m, 0.7H), 3.11-3.20 (m, 0.7H),2.93-3.07 (m, 1.3H), 2.40-2.49 (m, 1H), 1.17 (t, 3H), 1.00-1.05 (m, 3H).

Example 158D 4-Hydroxy-3-methylpyrrolidin-2-one (Diastereomer Mixture)

To a solution of 397 mg (1.34 mmol) of ethyl4-{[(benzyloxy)carbonyl]amino}-3-hydroxy-2-methylbutanoate in 7.2 ml ofmethanol were added 40 mg of palladium on charcoal (10%), andhydrogenation was effected at standard pressure and room temperature for6 h. The reaction mixture was then filtered through a Millipore filterand the solvent was removed under reduced pressure. 211 mg(quantitative) of the target compound were obtained, which were usedwithout further purification in the next step.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: −0.008 (0.80), 0.936 (15.27), 0.954(16.00), 0.985 (4.68), 1.002 (5.72), 1.010 (9.61), 1.021 (1.34), 1.028(9.33), 1.038 (1.50), 1.055 (2.69), 1.073 (1.35), 1.158 (4.92), 1.176(10.33), 1.194 (5.03), 2.004 (1.14), 2.022 (1.44), 2.039 (1.10), 2.225(1.59), 2.239 (1.71), 2.243 (1.63), 2.257 (1.57), 2.479 (1.15), 2.854(1.16), 2.868 (1.22), 2.878 (1.29), 2.893 (1.32), 2.958 (1.71), 2.962(2.91), 2.966 (1.63), 2.984 (1.89), 2.988 (3.22), 2.992 (1.80), 3.317(5.99), 3.329 (6.86), 3.333 (5.11), 3.336 (4.95), 3.343 (6.27), 3.350(4.61), 3.355 (6.03), 3.360 (3.76), 3.374 (3.03), 3.377 (2.85), 3.414(1.25), 3.431 (1.52), 3.449 (1.35), 3.847 (1.23), 3.862 (1.17), 4.018(1.05), 4.035 (2.89), 4.053 (2.81), 4.071 (0.94), 4.194 (1.14), 4.207(1.95), 4.219 (1.09), 7.419 (1.14).

Example 159A7-Chloro-N-(1,1,1,3,3,3-hexafluoro-2-methylpropan-2-yl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

To a solution of 150 mg (423 μmol) of the compound from Example 100B,91.9 mg (508 μmol) of 1,1,1,3,3,3-hexafluoro-2-methylpropan-2-amine and220 μl (1.30 mmol) of DIPEA in 1.6 ml of ethyl acetate were addeddropwise 740 μl (1.30 mmol) of2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide (T3P,50% in DMF). The mixture was stirred at 80° C. overnight and another 370μl (0.65 mmol) of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane2,4,6-trioxide (T3P, 50% in DMF) were added. The reaction mixture wasstirred at 80° C. for a further 64 h and the solvent was then removedunder reduced pressure. The residue was dissolved in acetonitrile, alittle water and formic acid, filtered through a Millipore filter andpurified by means of preparative HPLC (column: Chromatorex C18, 10 μm,125*40 mm, solvent: acetonitrile, water, 0.1% formic acid). 76.3 mg (35%of theory) of the title compound were obtained.

LC-MS (Method 3): R_(t)=2.46 min; MS (ESIpos): m/z=518 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.96 (s, 1H), 9.18 (s, 1H), 8.79 (d,1H), 7.80 (d, 1H), 7.62 (t, 2H), 2.08 (s, 3H).

Example 160A7-Chloro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carbonylchloride

To a solution of 800 mg (2.26 mmol) of the compound from Example 100B in18 ml of THF were added 490 μl (6.70 mmol) of thionyl chloride and themixture was stirred under reflux for a further 2 h, and then all thevolatile components were removed under reduced pressure. The crudeproduct was used in the next step without further workup (conversion wasassumed to be quantitative).

Example 160B7-Chloro-N-(2,6-dichlorophenyl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

To a solution of 840 mg (2.25 mmol) of7-chloro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carbonylchloride in 47 ml of dichloromethane were added, at RT, 940 μl (6.80mmol) of triethylamine and 438 mg (2.70 mmol) of 2,6-dichloroaniline.The mixture was stirred at RT for 30 min and at 50° C. overnight. Thereaction mixture was concentrated and taken up in dichloromethane,washed twice with 1 M aqueous hydrochloric acid, dried over magnesiumsulphate and filtered, and the solvent was removed under reducedpressure. The crude product was purified by means of normal phasechromatography (ethyl acetate/cyclohexane=1/1). 544 mg (48% of theory,99% purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=2.35 min; MS (ESIpos): m/z=498 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=11.34 (s, 1H), 9.22 (s, 1H), 8.81 (d,1H), 7.81 (d, 1H), 7.58-7.65 (m, 4H), 7.36-7.43 (m, 1H).

Example 161A7-(3-Methoxy-3-methylazetidin-1-yl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid

According to GP3, 91.3 mg (257 μmol) of the compound from Example 100Bwere reacted with 42.5 mg (309 μmol) of 3-methoxy-3-methylazetidinehydrochloride in the presence of 160 μl (900 μmol) of DIPEA in 1.2 ml ofDMF. The reaction was ended by adding acetonitrile, a little water andformic acid, the mixture was filtered through a Millipore filter, thecrude solution was purified by means of preparative HPLC (column:Chromatorex C18, 10 μm, 125*40 mm, solvents: acetonitrile, water, 0.1%formic acid), and 72.4 mg (63% of theory, 93% purity) of the titlecompound were obtained.

LC-MS (Method 3): R_(t)=1.83 min; MS (ESIpos): m/z=420 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=15.14 (br s, 1H), 9.01 (s, 1H), 8.32(d, 1H), 7.52-7.60 (m, 2H), 6.70 (d, 1H), 3.48-4.18 (m, 4H), 3.16 (s,3H), 1.41 (s, 3H).

Example 162A (3S,4S)-1-Benzyl-3,4-bis {[tert-butyl(dimethyl)silyl]oxy}pyrrolidine-2,5-dione

To a solution of 1.03 g (4.65 mmol) of(3S,4S)-1-benzyl-3,4-dihydroxypyrrolidine-2,5-dione and 949 mg (13.9mmol) of imidazole in 19.2 ml of DMF were added 1.76 g (11.7 mmol) oftert-butyldimethylsilyl chloride, and the reaction mixture was stirredat room temperature for 3 h. The reaction was admixed with water andextracted three times with dichloromethane. The organic phase was washedwith water, dried over magnesium sulphate and filtered, and the solventwas removed under reduced pressure. The residue was purified by means ofnormal phase chromatography (ethyl acetate/cyclohexane=1/4). This gave1.57 g (75% of theory) of the title compound.

¹H NMR (400 MHz, DMSO-d6): δ [ppm]=7.25-7.36 (m, 5H), 4.80 (s, 2H), 4.53(dd, 2H), 0.91 (s, 18H), 0.17 (s, 6H), 0.13 (s, 6H).

Example 162B (3R,4R)-1-Benzyl-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}pyrrolidine

To a solution of 1.57 g (3.49 mmol) of (3S,4S)-1-benzyl-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}pyrrolidine-2,5-dione in 11.3 ml of THFat 0° C. were added dropwise 9.1 ml (1.00 M, 9.10 mmol) ofborane-tetrahydrofuran complex, and the reaction mixture was stirred atroom temperature for 2.5 h and under reflux for 2 h. The solvent wasremoved on a rotary evaporator and the residue was dissolved in 7 ml ofethanol. The mixture was stirred under reflux for 21 h. Subsequently,the mixture was concentrated by evaporation on a rotary evaporator, andwater and diethyl ether were added. The organic phase was extractedthree times with diethyl ether. The combined organic phases were washedwith saturated sodium chloride solution, dried over sodium sulphate andconcentrated. The residue was purified by means of normal phasechromatography (ethyl acetate-cyclohexane gradient). 711 mg (46% oftheory, 95% purity) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.07 min; MS (ESIpos): m/z=422 [M+H]⁺

¹H NMR (400 MHz, CDCl3): δ [ppm]=7.22-7.35 (m, 5H), 4.07-4.15 (m, 2H),3.62 (dd, 2H), 2.87 (dd, 2H), 2.43-2.48 (m, 2H), 0.87-0.90 (m, 18H),0.06 (s, 6H), 0.01-0.05 (m, 6H).

Example 162C (3R,4R)-3,4-Bis {[tert-butyl(dimethyl)silyl]oxy}pyrrolidine

To a solution of 711 mg (1.69 mmol) of(3R,4R)-1-benzyl-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}pyrrolidine in7.7 ml of ethanol were added 71.1 mg (506 μmol) of palladium(II)hydroxide, and hydrogenation was effected at standard pressure and roomtemperature for 2.5 h. The reaction mixture was then filtered throughkieselguhr and the solvent was removed under reduced pressure. 582 mg(quantitative) of the title compound were obtained, which were usedwithout further purification in the next step.

¹H NMR (400 MHz, DMSO-d6): δ [ppm]=4.26-4.39 (m, 1H), 3.90-3.94 (m, 2H),3.40-3.49 (m, 1H), 2.94-3.01 (m, 2H), 0.85 (s, 18H), 0.05 (s, 6H), 0.04(s, 6H).

Example 163A Ethyl 4-{[(benzyloxy)carbonyl]amino}-3-oxopentanoate(Racemate)

To a solution of 15.0 g (71.7 mmol) ofN-[(benzyloxy)carbonyl]-DL-alanine in 200 ml of THF were added 3.46 g(21.3 mmol) of carbonyldiimidazole (CDI), and the mixture was stirred atRT for a further 2.5 h. Subsequently, while cooling with an ice bath,3.63 g (21.3 mmol) of potassium 3-ethoxy-3-oxopropanoate and 1.86 g(19.5 mmol) of magnesium chloride were added. On completion of addition,stirring was continued at 50° C. overnight. Ethyl acetate and saturatedaqueous ammonium chloride solution were added, and the phases wereseparated. The organic phase was washed with saturated aqueous sodiumchloride solution, dried over sodium sulphate and filtered, and thesolvent was removed under reduced pressure. The residue was purified bymeans of normal phase chromatography (ethyl acetate-cyclohexanegradient), and 2.90 g (37% of theory) of the title compound wereobtained.

LC-MS (Method 3): R_(t)=1.63 min; MS (ESIneg): m/z=292 [M−H]⁻

¹H NMR (400 MHz, DMSO-d₆): δ ppm=7.74 (br d, 1H), 7.25-7.43 (m, 5H),5.04 (s, 2H), 4.12-4.21 (m, 1H), 4.00-4.12 (m, 2H), 3.54-3.67 (m, 2H),1.14-1.22 (m, 6H).

Example 163B Ethyl 4-{[(benzyloxy)carbonyl]amino}-3-hydroxypentanoate(Diastereomer Mixture)

To a solution of 1.0 g (3.41 mmol) of ethyl4-{[(benzyloxy)carbonyl]amino}-3-oxopentanoate in 18 ml of methanol wereadded, at 0° C., 181 mg (4.77 mmol) of sodium borohydride. The mixturewas warmed gradually to RT and stirred at RT for a further 2 h. Thereaction was ended by adding saturated aqueous ammonium chloridesolution. The organic phase was extracted three times with ethylacetate. The combined organic phases were washed with saturated aqueoussodium chloride solution, dried over magnesium sulphate and filtered,and the solvent was removed under reduced pressure. The residue wastaken up in a little acetonitrile and purified by means of preparativeHPLC (column: Chromatorex C18, 10 m, 125*40 mm, solvent: acetonitrile,water, 0.1% formic acid). 398 mg (40% of theory) of the title compoundwere obtained.

LC-MS (Method 1): R_(t)=0.79 min; MS (ESIpos): m/z=296 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=7.27-7.39 (m, 5H), 7.08 (br d, 0.75H),6.97 (br d, 0.25H), 4.97-5.04 (m, 2H), 4.89-4.97 (m, 1H), 4.04 (q, 2H),3.84-3.90 (m, 0.25H), 3.72-3.80 (m, 0.75H), 3.55-3.65 (m, 0.25H),3.38-3.50 (m, 0.75H), 2.39-2.47 (m, 2H), 2.16-2.25 (m, 1H), 1.17 (t,3H), 0.98-1.06 (m, 3H).

Example 163C 4-Hydroxy-5-methylpyrrolidin-2-one (Diastereomer Mixture)

To a solution of 398 mg (1.35 mmol) of ethyl4-{[(benzyloxy)carbonyl]amino}-3-hydroxypentanoate in 6.8 ml of methanolwere added 34 mg of palladium on charcoal (10%), and hydrogenation waseffected at standard pressure and room temperature for 5 h. The reactionmixture was then filtered through a Millipore filter and the solvent wasremoved under reduced pressure. 152 mg (98% of theory) of the titlecompound were obtained, which were used without further purification inthe next step.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.922 (1.20), 0.938 (1.18), 1.022(4.00), 1.038 (5.02), 1.054 (16.00), 1.071 (15.05), 1.162 (0.96), 1.180(1.95), 1.198 (0.96), 1.911 (2.63), 1.922 (2.66), 1.928 (0.88), 1.936(0.72), 1.953 (3.08), 1.964 (3.16), 1.969 (1.02), 1.977 (0.79), 2.358(0.76), 2.373 (0.78), 2.399 (0.72), 2.412 (3.05), 2.429 (2.91), 2.454(2.51), 2.471 (2.81), 3.272 (1.56), 3.274 (1.65), 3.280 (1.80), 3.282(1.89), 3.288 (2.04), 3.290 (2.15), 3.296 (2.48), 3.298 (2.71), 3.313(14.07), 3.793 (1.26), 3.801 (1.51), 3.810 (1.48), 3.819 (1.12), 4.038(0.90), 4.056 (0.89), 4.923 (0.86), 4.934 (0.81), 5.163 (2.76), 5.174(2.65), 7.588 (1.18).

Example 164A Ethyl4-{[(benzyloxy)carbonyl]amino}-2,2-dimethyl-3-oxopentanoate (Racemate)

A suspension of 500 mg (1.70 mmol) of ethyl4-{[(benzyloxy)carbonyl]amino}-3-oxopentanoate, 320 μl (5.10 mmol) ofiodomethane and 471 mg (3.41 mmol) of potassium carbonate in 7.2 ml ofacetone was reacted in a microwave at 60° C. for 16 h. The reactionmixture was poured into water and extracted three times with ethylacetate. The combined organic phases were washed with saturated aqueoussodium chloride solution, dried over sodium sulphate and filtered, andthe solvent was removed under reduced pressure. The residue wasdissolved in a little acetonitrile, filtered through a Millipore filterand separated in two runs by means of preparative HPLC (column:Chromatorex C18, 10 μm, 125*40 mm, solvent: acetonitrile, water, 0.1%formic acid). 260 mg (47% of theory) of the title compound wereobtained.

LC-MS (Method 3): R_(t)=1.92 min; MS (ESIpos): m/z=322 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=7.65 (br d, 1H), 7.26-7.42 (m, 5H),5.01 (s, 2H), 4.51 (quint., 1H), 4.06 (q, 2H), 1.35 (s, 3H), 1.29 (s,3H), 1.11-1.18 (m, 6H).

Example 164B Ethyl4-{[(benzyloxy)carbonyl]amino}-2,2-dimethyl-3-hydroxypentanoate(Diastereomer 2)

To a solution of 260 mg (809 μmol) of ethyl4-{[(benzyloxy)carbonyl]amino}-2,2-dimethyl-3-oxopentanoate in 4.5 ml ofmethanol were added, at 0° C., 42.9 mg (1.13 mmol) of sodiumborohydride. The mixture was warmed gradually to RT and stirred at RTfor a further 17 h. The reaction was ended by adding saturated aqueousammonium chloride solution. The organic phase was extracted three timeswith ethyl acetate. The combined organic phases were washed withsaturated aqueous sodium chloride solution, dried over magnesiumsulphate and filtered, and the solvent was removed under reducedpressure. The residue was taken up in a little acetonitrile and purifiedby means of preparative HPLC (column: Chromatorex C18, 10 μm, 125*40 mm,solvent: acetonitrile, water, 0.1% formic acid). 64.0 mg (24% of theory,100% purity) of the title compound (Diastereomer 2) were obtained. 95.0mg (34% of theory, 93% purity) of diastereomer 1 were obtained.

LC-MS (Method 3): R_(t)=1.71 min; MS (ESIpos): m/z=324 [M+H]⁺

Example 164C 4-Hydroxy-3,3,5-trimethylpyrrolidin-2-one (Racemate)

To a solution of 64.0 mg (198 μmol) of ethyl4-{[(benzyloxy)carbonyl]amino}-2,2-dimethyl-3-hydroxypentanoate(Diastereomer 2) in 1.0 ml of methanol were added 5 mg of palladium oncharcoal (10%), and hydrogenation was effected at standard pressure androom temperature for 6 h. The reaction mixture was then filtered througha Millipore filter and the solvent was removed under reduced pressure.20.0 mg (71% of theory) of the title compound were obtained, which wereused without further purification in the next step.

¹H NMR (400 MHz, CDCl3): δ ppm=5.54 (br s, 1H), 3.85-3.92 (m, 2H), 2.62(s, 1H), 1.27 (d, 3H), 1.20 (s, 3H), 1.19 (s, 3H).

Example 165A7-[(3R,4R)-3,4-Bis{[tert-butyl(dimethyl)silyl]oxy}pyrrolidin-1-yl]-1-(2,6-difluorophenyl)-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP3, 75.0 mg (168 μmol) of the compound from Example 86Awere reacted with 67.0 mg (202 μmol) of the compound from Example 162Cin the presence of 100 μl (590 μmol) of DIPEA in 750 μl of DMF. Thesolvent was removed under reduced pressure and the crude product waspurified by means of normal phase chromatography (ethylacetate-cyclohexane gradient). 119 mg (95% of theory, 95% purity) of thetitle compound were obtained.

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.42 (d, 1H), 8.78 (s, 1H), 8.30 (d,1H), 7.70 (tt, 1H), 7.32-7.43 (m, 2H), 6.82 (d, 1H), 4.69-4.80 (m, 1H),4.15-4.21 (m, 1H), 4.00-4.07 (m, 1H), 3.68 (br dd, 1H), 3.21-3.29 (m,2H), 3.03-3.11 (m, 1H), 1.83-1.93 (m, 1H), 1.58-1.70 (m, 1H), 0.97 (t,3H), 0.83 (s, 9H), 0.79 (s, 9H), 0.08 (s, 6H).

Example 166A Ethyl7-chloro-1-(2,6-dichlorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate

To a solution of 6.07 g (19.1 mmol) of ethyl2-[(2,6-dichloropyridin-3-yl)carbonyl]-3-ethoxyacrylate (CAS157373-27-8) and 4.33 g (26.7 mmol) of 2,6-dichloroaniline in 30 ml DCMwere added 23 ml (130 mmol) of N,N-diisopropylethylamine, and themixture was stirred at room temperature for 4 h. Subsequently, 2.64 g(19.1 mmol) of potassium carbonate were added to the reaction mixtureand the reaction was heated under reflux for 4 d. The mixture was cooleddown to RT, diluted with dichloromethane, and washed twice with 1 Maqueous hydrochloric acid and once with saturated aqueous sodiumchloride solution. The organic phase was dried over sodium sulphate andfiltered, and the solvent was removed under reduced pressure. Theresidue was stirred with diethyl ether and the precipitate was filteredoff with suction and dried under high vacuum. Dichloromethane andmethanol (1:1, v/v) were added to the substance. The mixture was boiledbriefly and the precipitate was filtered off with suction. The motherliquor was concentrated and precipitating solid was filtered off withsuction once again. 2.83 g (37% of theory, 100% purity) of the titlecompound were obtained.

LC-MS (Method 3): R_(t)=1.89 min; MS (ESIpos): m/z=396 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=8.85 (s, 1H), 8.65 (d, 1H), 7.77-7.82(m, 2H), 7.65-7.72 (m, 2H), 4.25 (q, 2H), 1.28 (t, 3H).

Example 166B7-Chloro-1-(2,6-dichlorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid

To a suspension of 2.78 g (7.00 mmol) of the compound from Example 166Ain 23 ml of water were successively added 23 ml of concentratedhydrochloric acid and 23 ml of tetrahydrofuran. The resulting suspensionwas stirred vigorously at 120° C. for 30 h and subsequently cooled downto RT. The mixture was diluted with 150 ml of water, and the precipitatewas filtered off with suction and dried under high vacuum. 2.49 g (96%of theory, 100% purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.91 min; MS (ESIpos): m/z=368 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=13.82 (br s, 1H), 9.22 (s, 1H), 8.81(d, 1H), 7.78-7.84 (m, 3H), 7.70 (dd, 1H).

Example 166C7-Chloro-1-(2,6-dichlorophenyl)-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 400 mg (1.08 mmol) of7-chloro-1-(2,6-dichlorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid were reacted with 266 mg (1.62 mmol) of(2R)-1,1,1-trifluorobutan-2-amine hydrochloride in the presence of 494mg (1.30 mmol) of HATU and 570 μl (3.20 mmol) of DIPEA in 6.0 ml of DMF.The mixture was diluted with water, 1 M aqueous hydrochloric acid andethyl acetate. The phases were separated and the organic phase wasremoved under reduced pressure. The crude product was suspended inacetonitrile and the precipitate (116.5 mg of the title compound) wasfiltered off. The mother liquor was purified by means of preparativeHPLC (column: Chromatorex C18, 10 m, 125*40 mm, solvent: acetonitrile,water, 0.1% formic acid), and, combined with the precipitate, a total of304 mg (59% of theory, 99% purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=2.40 min; MS (ESIpos): m/z=478 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ ppm=9.91 (d, 1H), 9.04 (s, 1H), 8.78 (d,1H), 7.77-7.83 (m, 3H), 7.67-7.73 (m, 1H), 4.70-4.83 (m, 1H), 1.85-1.95(m, 1H), 1.60-1.75 (m, 1H), 0.98 (t, 3H).

Example 167A7-[(3R,4R)-3,4-Bis{[tert-butyl(dimethyl)silyl]oxy}pyrrolidin-1-yl]-1-(2,4-difluorophenyl)-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to General Procedure 3, 100 mg (224 μmol) of the compound fromExample 67A were reacted with 89.3 mg (269 μmol) of the compound fromExample 162C in the presence of 140 μl (790 μmol) of DIPEA in 1.0 ml ofDMF. The solvent was removed under reduced pressure and the crudeproduct was purified by means of normal phase chromatography (ethylacetate-cyclohexane gradient). 166 mg (quantitative) of the titlecompound were obtained.

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.50 (d, 1H), 8.64 (d, 1H), 8.29 (d,1H), 7.74-7.86 (m, 1H), 7.42-7.58 (m, 1H), 7.26-7.35 (m, 1H), 6.80 (d,1H), 4.68-4.79 (m, 1H), 4.18 (br s, 1H), 4.05 (br s, 1H), 3.63-3.73 (m,1H), 3.22-3.30 (m, 2H), 2.95-3.17 (m, 1H), 1.83-1.93 (m, 1H), 1.58-1.69(m, 1H), 0.96 (t, 3H), 0.76-0.86 (m, 18H), 0.08 (s, 6H), −0.03-0.05 (m,6H).

Example 168A7-(4-Carbamoylpiperazin-1-yl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid

According to General Procedure 3, 500 g (1.41 mmol) of7-chloro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid (Example 100B) were reacted with 219 mg (1.69 mmol) ofpiperazine-1-carboxamide in the presence of 860 μl (4.90 mmol) of DIPEAin 6.3 ml of DMF. The precipitate (358 mg of the title compound) wasfiltered out of the reaction mixture and the mother liquor was purifiedby means of preparative HPLC (acetonitrile/water/0.1% formic acid).Combined with the precipitate, 418 mg (67% of theory, 100% purity) ofthe title compound were obtained.

LC-MS (Method 1): R_(t)=0.70 min; MS (ESIpos): m/z=448 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=15.09 (br s, 1H), 9.04 (s, 1H), 8.34(d, 1H), 7.59 (t, 2H), 7.23 (d, 1H), 6.04 (s, 2H), 3.44-3.59 (m, 4H).

Example 169A(5S)-3-[6-{[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]carbamoyl}-5-oxo-8-(2,4,6-trifluorophenyl)-5,8-dihydro-1,8-naphthyridin-2-yl]-2-oxo-1,3-oxazolidine-5-carbonylchloride

To a solution of 317 mg (556 μmol) of the compound from Example 667 in7.0 ml of dichloromethane were added 410 μl (5.60 mmol) of thionylchloride, the mixture was stirred under reflux for a further 3 h, andanother 820 μl (11.2 mmol) of thionyl chloride were added. The reactionmixture was stirred under reflux overnight and then all volatilecomponents were removed under reduced pressure. The crude product wasused in the next step without further workup (conversion was assumed tobe quantitative).

Example 170A(5R)-3-[6-{[(15)-1-Cyclopropyl-2,2,2-trifluoroethyl]carbamoyl}-5-oxo-8-(2,4,6-trifluorophenyl)-5,8-dihydro-1,8-naphthyridin-2-yl]-2-oxo-1,3-oxazolidine-5-carbonylchloride

To a solution of 440 mg (771 μmol) of the compound from Example 670 in10 ml of dichloromethane were added 560 μl (7.70 mmol) of thionylchloride, the mixture was stirred under reflux for a further 3 h, andanother 1.12 ml (15.4 mmol) of thionyl chloride were added. The reactionmixture was stirred under reflux overnight and then all volatilecomponents were removed under reduced pressure. The crude product wasused in the next step without further workup (conversion was assumed tobe quantitative).

WORKING EXAMPLES Example 11-(2,4-Difluorophenyl)-7-(3,3-difluoropiperidin-1-yl)-4-oxo-N-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

A mixture of 80 mg (0.17 mmol) of the compound from Example 65A, 54 mg(0.34 mmol) of 3,3-difluoropiperidine hydrochloride and 88 mg (0.68mmol) of DIPEA in 1.5 ml of NMP was stirred at 23° C. for 2 h.Subsequently, the mixture was purified via preparative HPLC (Method 7).This gave 43 mg (45% of theory) of the title compound.

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.008 (1.85), 0.008 (1.65), 1.609(0.87), 1.620 (1.04), 1.673 (7.07), 2.011 (0.49), 2.029 (0.86), 2.058(16.00), 2.073 (2.19), 2.366 (0.53), 2.710 (0.50), 3.534 (0.91), 3.546(1.26), 3.562 (0.86), 3.824 (0.46), 3.841 (0.59), 3.855 (0.75), 3.885(0.41), 7.185 (1.64), 7.208 (1.68), 7.339 (0.69), 7.348 (0.66), 7.568(0.46), 7.575 (0.47), 7.590 (0.61), 7.597 (0.72), 7.600 (0.63), 7.616(0.46), 7.623 (0.45), 7.779 (0.44), 7.795 (0.53), 7.802 (0.90), 7.816(0.89), 7.823 (0.51), 7.839 (0.42), 8.295 (2.38), 8.318 (2.19), 8.514(4.49), 9.883 (2.53).

LC-MS (Method 1): R_(t)=1.34 min; m/z=479.2 [M+H]⁺.

In analogy to Example 1, the example compounds shown in Table 1 wereprepared by reacting the compound from Example 65A with the appropriateamines (or salts thereof) under the reaction conditions described.Differences are specified in the respective examples.

TABLE 1 Ex. Analytical data 2 7-(6,6-Difluoro-3-azabicylco[3.1.0]hex-3-LC-MS (Method 1): R_(t) = 1.42 minyl)-1-(2,4-difluorophenyl)-4-oxo-N-(tricyclo MS (ESpos): m/z = 553.4[M + H]⁺ [3.3.1.1^(3,7)]dec-1-yl)-1,4-dihydro-1,8- ¹H-NMR (400 MHz,DMSO-d₆): δ = 1.67 naphthyridine-3-carboxamide (m, 6 H), 2.06 (m, 9H),2.58-2.77 (m, 2H, partially overlapping with DMSO signal),

3.44 (br. s, 2H), 3.80 (br. s., 2H), 6.74 (d, 1H), 7.29-7.36 (m, 1H),7.53-7.64 (m, 1H), 7.76-7.84 (m, 1H), 8.30 (d, 1H), 8.50 (s, 1H), 9.91(br. s, 1H). (92% of theory) 31-(2,4-Difluorophenyl)-7-[(3R,4R)-4-fluoro- LC-MS (Method 1): R_(t) =1.26 min 3-hydroxypiperidin-1-yl]-4-oxo-N-(tricyclo MS (ESpos): m/z =553.4 [M + H]⁺ [3.3.1.1^(3,7)]dec-1-yl)-1,4-dihydro-1,8- ¹H-NMR (400MHz, DMSO-d₆): δ = 1.39- naphthyridine-3-carboxamide 1.55 (m, 1H), 1.68(s, 6 H), 1.88-2.01 (m, 1H), 2.06 (m, 9H), 2.90-3.09 (m, 1H),

3.11-3.27 (m, 2H), 3.38-3.51 (m, 2H), 4.36-4.45 (m, 1H), 4.48-4.59 (m,1H), 5.41-5.49 (m, 2H), 7.11 (d, 1H), 7.29-7.36 (m, 1H), 7.52-7.62 (m,1H), 7.77-7.84 (m, 1H), 8.28 (d, 1H), 8.49 (s, 1H), 9.91 (br. s, 1H).(80% of theory) 4 Methyl 4-[8-(2,4-difluorophenyl)-5-oxo-6- LC-MS(Method 1): R_(t) = 1.30 min(tricyclo[3.3.1.1^(3,7)]dec-1-ylcarbamoyl)-5,8- MS (ESpos): m/z = [M +H]⁺ dihydro-1,8-naphthyridin-2-yl]piperazine-1- ¹H-NMR (400 MHz,DMSO-d₆) δ [ppm]: carboxylate −0.008 (1.17), 0.008 (0.97), 1.157 (1.26),1.175 (2.57), 1.193 (1.30), 1.672 (7.47),

1.988 (4.65), 2.055 (16.00), 3.360 (1.42), 3.374 (3.07), 3.388 (2.46),3.493 (2.28), 3.506 (2.93), 3.520 (1.59), 3.603 (13.90), 4.021 (1.08),4.038 (1.07), 7.070 (2.00), 7.093 (2.02), 7.308 (0.42), 7.325 (0.78),7.332 (0.76), 7.334 (0.61), 7.344 (0.41), 7.348 (0.43), 7.351 (0.45),7.354 (0.40), 7.555 (0.52), 7.562 (0.55), 7.578 (0.70), 7.581 (0.76),7.585 (0.78), 7.589 (0.65), 7.604 (0.54), 7.611 (0.52), 7.761 (0.51),7.775 (0.61), 7.782 (1.00), 7.797 (1.01), 7.804 (0.56), 7.819 (0.49),8.297 (2.65), 8.319 (2.43), 8.503 (5.19), 9.897 (2.86). (74% of theory)5 1-(2,4-Difluorophenyl)-7-(4-fluoropiperidin- LC-MS (Method 1): R_(t) =1.38 min 1-yl)-4-oxo-N-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)- MS (ESpos):m/z = 537.5 [M + H]⁺ 1,4-dihydro-1,8-naphthyridine-3-carboxamide ¹H-NMR(400 MHz, DMSO-d₆) δ [ppm]: 1.670 (8.34), 1.828 (0.58), 2.055 (16.00),

2.365 (0.20), 2.710 (0.19), 3.494 (1.01), 3.602 (0.95), 4.797 (0.41),4.919 (0.41), 7.124 (1.42), 7.147 (1.47), 7.309 (0.45), 7.330 (0.88),7.351 (0.49), 7.562 (0.47), 7.584 (0.83), 7.604 (0.48), 7.772 (0.40),7.794 (0.82), 7.809 (0.82), 7.830 (0.38), 8.272 (1.60), 8.295 (1.52),8.493 (3.05), 9.909 (2.30) (81% of theory) 67-(3,3-Difluoro-4,4-dihydroxypiperidin-1- LC-MS (Method 1): R_(t) = 1.17min yl)-1-(2,4-difluorophenyl)-4-oxo-N-(tricyclo MS (ESpos): m/z = 587.4[m + H]⁺ [3.3.1.1^(3,7)]dec-1-yl)-1,4-dihydro-1,8- ¹H-NMR (400 MHz,DMSO-d₆) δ [ppm]: naphthyridine-3-carboxamide 1.003 (5.12), 1.020(4.58), 1.174 (1.24), 1.671 (8.60), 1.987 (2.21), 2.057 (16.00),

3.560 (1.43), 3.824 (0.84), 6.433 (1.52), 7.197 (1.18), 7.220 (1.24),7.346 (0.81), 7.594 (0.81), 7.798 (0.93), 7.813 (0.94), 8.191 (1.88),8.294 (2.21), 8.317 (2.03), 8.516 (4.68), 9.880 (2.69). (18% of theory)7 1-(2,4-Difluorophenyl)-7-[(3R)-3-fluoro-4,4- LC-MS (Method 1): R_(t) =1.10 min dihydroxypiperidin-1-yl]-4-oxo-N-(tricyclo MS (ESpos): m/z =569.5 [M + H]⁺ [3.3.1.1^(3,7)]dec-1-yl)-1,4-dihydro-1,8- ¹H-NMR (400MHz, DMSO-d₆) δ [ppm]: naphthyridine-3-carboxamide 0.976 (1.80), 0.992(1.66), 1.507 (0.39), 1.537 (0.33), 1.671 (8.13), 2.057 (16.00),

2.328 (0.30), 2.366 (0.39), 2.670 (0.34), 2.711 (0.38), 3.026 (0.31),3.168 (0.84), 3.934 (0.41), 3.964 (0.41), 4.152 (0.42), 4.229 (0.43),4.264 (0.69), 5.946 (0.85), 5.959 (0.93), 6.045 (1.02), 7.105 (1.27),7.128 (1.32), 7.317 (0.44), 7.337 (0.85), 7.354 (0.47), 7.559 (0.44),7.566 (0.48), 7.585 (0.77), 7.608 (0.46), 7.615 (0.43), 7.782 (0.45),7.799 (0.65), 7.815 (0.42), 8.209 (0.39), 8.247 (1.41), 8.270 (1.34),8.486 (2.39), 9.915 (2.26). (10% of theory) 81-(2,4-Difluorophenyl)-4-oxo-7-(piperidin-1- LC-MS (Method 1): R_(t) =1.48 min yl)-N-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)-1,4- MS (ESpos): m/z =519.4 [M + H]⁺ dihydro-1,8-naphthyridine-3-carboxamide ¹H-NMR (400 MHz,DMSO-d₆) δ [ppm]: −0.001 (14.80), 0.938 (0.69), 0.953 (0.65),

1.427 (2.32), 1.578 (1.22), 1.670 (7.45), 2.054 (16.00), 2.365 (0.41),2.694 (0.59), 2.709 (0.44), 3.470 (2.58), 7.048 (1.93), 7.071 (1.98),7.301 (0.42), 7.323 (0.81), 7.343 (0.44), 7.545 (0.51), 7.552 (0.54),7.574 (0.76), 7.593 (0.52), 7.600 (0.49), 7.760 (0.50), 7.782 (0.99),7.797 (0.99), 7.819 (0.49), 8.227 (2.51), 8.250 (2.35), 8.466 (5.28),9.935 (2.69). (73% of theory) 9rac-1-(2,4-Difluorophenyl)-7-(3-fluoro-3- LC-MS (Method 1): R_(t) = 1.43min methylpyrrolidin-1-yl)-4-oxo-N-(tricyclo MS (ESpos): m/z = 537.4[M + H]⁺ [3.3.1.1^(3,7)]dec-1-yl)-1,4-dihydro-1,8- ¹H NMR (400 MHz,DMSO-d₆) δ [ppm]: naphthyridine-3-carboxamide −0.150 (0.31), −0.009(2.72), 0.007 (2.36), 0.146 (0.29), 1.243 (0.52), 1.258 (0.65),

1.272 (0.33), 1.508 (0.80), 1.671 (7.35), 1.987 (0.32), 2.056 (16.00),2.212 (0.24), 2.322 (0.25), 2.327 (0.34), 2.365 (1.68), 2.518 (1.52),2.523 (2.13), 2.557 (0.97), 2.560 (0.88), 2.562 (0.73), 2.564 (0.52),2.567 (0.41), 2.569 (0.47), 2.577 (0.26), 2.580 (0.27), 2.660 (0.25),2.665 (0.33), 2.669 (0.45), 2.674 (0.29), 2.694 (0.21), 2,709 (1.76),3.144 (0.22), 3.161 (0.59), 3.174 (0.64), 3.195 (0.19), 3.217 (0.19),3.380 (0.28), 3.431 (0.22), 3.448 (0.25), 3.459 (0.24), 3.472 (0.21),3.507 (0.25), 3.681 (0.22), 6.722 (0.27), 7.301 (0.33), 7.322 (0.64),7.341 (0.38), 7.550 (0.25), 7.573 (0.46), 7.764 (0.29), 7.786 (0.62),7.800 (0.60), 7.823 (0.27), 8.283 (0.75), (85% of theory) 8.305 (0.75),8.482 (3.76), 9.934 (2.64). 107-(3-Cyanopiperidin-1-yl)-1-(2,4-difluoro- LC-MS (Method 1): R_(t) =1.27 min phenyl)-4-oxo-N-(tricyclo[3.3.1.1^(3,7)]dec-1- MS (ESpos): m/z= 544.3 [M + H]⁺ yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide ¹H-NMR(400 MHz, DMSO-d₆) δ [ppm]: 0.936 (1.41), 0.951 (1.34), 1.235 (0.32),

1.475 (0.40), 1.558 (0.43), 1.672 (7.37), 1.862 (0.58), 1.882 (1.03),1.901 (1.49), 1.920 (1.32), 1.937 (0.61), 2.057 (16.00), 2.155 (1.02 ),2.176 (1.43), 2.195 (0.76), 2.327 (0.29), 2.669 (0.31), 2.694 (6.05),2.961 (0.60), 3.285 (2.06), 3.477 (0.41), 3.561 (0.38), 3.680 (0.35),3.713 (0.77), 3.743 (0.54), 3.760 (0.53), 7.166 (1.68), 7.189 (1.72),7.321 (0.53), 7.555 (0.54), 7.575 (0.53), 7.786 (0.49), 7.802 (0.58),7.822 (0.46), 8.292 (2.36), 8.315 (2.20), 8.514 (3.44), 9.891 (2.51).(87% of theory) 11 1-(2,4-Difluorophenyl)-7-[(2R,4S)-4-fluoro- LC-MS(Method 1): R_(t) = 1.43 min 2-methylpyrrolidin-1-yl]-4-oxo-N-(tricycloMS (ESpos): m/z = 537.4 [M + H]⁺[3.3.1.1^(3,7)]dec-1-yl)-1,4-dihydro-1,8- ¹H-NMR (400 MHz, DMSO-d₆) δ[ppm]: naphthyridine-3-carboxamide −0.150 (0.18), 0.145 (0.20), 0.840(0.16), 0.889 (0.59), 0.919 (0.47), 0.934 (2.34),

0.951 (2.23), 1.066 (0.31), 1.146 (0.27), 1.234 (0.18), 1.672 (7.79),1.901 (0.20), 1.959 (0.24), 2.058 (16.00), 2.218 (0.20), 2.327 (0.34),2.366 (1.39), 2.408 (0.22), 2.427 (0.23), 2.669 (0.35), 2.694 (0.24),2.709 (1.39), 2.960 (0.19), 3.584 (0.17), 3.915 (0.17), 5.326 (0.24),5.457 (0.24), 6.737 (0.27), 7.322 (0.66), 7.344 (0.38), 7.569 (0.46),7.592 (0.47), 7.767 (0.28), 7.788 (0.62), 7.804 (0.62), 7.825 (0.27),8.281 (1.86), 8.303 (1.78), 8.498 (1.45), 9.940 (2.44). (70% of theory)12 7-(4-Carbamoylpiperazin-1-yl)-1-(2,4- LC-MS (Method 1): R_(t) = 1.10min difluorophenyl)-4-oxo-N-(tricyclo MS (ESpos): m/z = 563.4 [M + H]⁺[3.3.1.1^(3,7)]dec-1-yl)-1,4-dihydro-1,8- ¹H-NMR (400 MHz, DMSO-d₆) δ[ppm]: naphthyridine-3-carboxamide −0.001 (0.96), 1.669 (1.15), 1.861(0.09), 1.881 (0.29), 1.901 (0.34), 1.916 (0.24),

1.919 (0.30), 1.937 (0.12), 2.055 (2.40), 2.155 (0.34), 2.175 (0.47),2.195 (0.24), 2.694 (2.11), 3.284 (0.84), 3.302 (1.37), 3.315 (16.00),3.453 (0.43), 6.021 (0.47), 7.083 (0.28), 7.106 (0.28), 7.314 (0.07),7.335 (0.12), 7.356 (0.07), 7.560 (0.08), 7.567 (0.09), 7.586 (0.12),7.608 (0.08), 7.615 (0.08), 7.770 (0.08), 7.785 (0.10), 7.792 (0.15),7.807 (0.15), 7.814 (0.08), 7.829 (0.07), 8.280 (0.38), 8.303 (0.35),8.497 (0.81), 9.907 (0.41). (quant. yield) 137-(1,1-Difluoro-5-azaspiro[2.4]hept-5-yl)-1- LC-MS (Method 1): R_(t) =1.46 min (2,4-difluorophenyl)-4-oxo-N-(tricyclo MS (ESpos): m/z = 567.4[M + H]⁺ [3.3.1.1^(3,7)]dec-1-yl)-1,4-dihydro-1,8- ¹H-NMR (400 MHz,DMSO-d₆) δ [ppm]: naphthyridine-3-carboxamide −0.150 (0.85), −0.009(8.08), 0.008 (6.51), 0.146 (0.85), 1.147 (0.31), 1.156 (0.33),

1.174 (0.66), 1.192 (0.37), 1.240 (0.31), 1.258 (0.33), 1.616 (0.81),1.622 (0.76), 1.636 (0.85), 1.672 (7.46), 1.988 (1.36), 2.056 (16.00),2.131 (0.39), 2.156 (0.37), 2.177 (0.37), 2.327 (0.66), 2.366 (3.16),2.608 (0.25), 2.669 (0.74), 2.673 (0.54), 2.694 (1.07), 2.709 (3.12),3.285 (1.30), 3.461 (0.33), 3.505 (0.29), 4.020 (0.31), 4.038 (0.31),6.742 (0.48), 6.765 (0.50), 7.293 (0.37), 7.307 (0.76), 7.330 (0.43),7.526 (0.39), 7.533 (0.37), 7.555 (0.68), 7.575 (0.39), 7.760 (0.35),7.780 (0.72), 7.796 (0.70), 7.816 (0.33), 8.291 (1.90), 8.313 (1.84),8.488 (4.22), 9.928 (2.71). (95% of theory) 14rac-1-(2,4-Difluorophenyl)-7-(3-hydroxy- LC-MS (Method 1): R_(t) = 1.19min piperidin-1-yl)-4-oxo-N-(tricyclo MS (ESpos): m/z = 535.3 [M + H]⁺[3.3.1.1^(3,7)]dec-1-yl)-1,4-dihydro-1,8- ¹H-NMR (400 MHz, DMSO-d₆) δ[ppm]: naphthyridine-3-carboxamide −0.009 (1.19), 0.007 (1.22), 0.942(0.31), 1.263 (0.83), 1.391 (0.47), 1.669 (7.58),

1.803 (0.43), 1.881 (0.20), 1.901 (0.21), 1.920 (0.19), 2.054 (16.00),2.155 (0.20), 2.176 (0.27), 2.195 (0.16), 2.327 (0.18), 2.366 (0.33),2.669 (0.23), 2.694 (1.18), 2.709 (0.39), 2.949 (0.25), 3.030 (0.21),3.057 (0.30), 3.090 (0.23), 3.126 (0.30), 3.154 (0.21), 3.285 (0.44),3.370 (0.20), 3.429 (0.42), 3.670 (0.32), 3.806 (0.27), 3.839 (0.46),3.869 (0.25), 4.796 (1.50), 4.808 (1.49), 7.027 (1.79), 7.050 (1.83),7.296 (0.38), 7.300 (0.42), 7.322 (0.82), 7.339 (0.44), 7.343 (0.46),7.558 (0.45), 7.757 (0.30), 7.779 (0.66), 7.795 (0.66), 7.816 (0.29),8.222 (1.38), 8.245 (1.32), 8.464 (4.15), 9.934 (2.51). (96% of theory)15 1-(2,4-Difluorophenyl)-7-[(2S)-2-(hydroxy- LC-MS (Method 1): Rt =1.29 min methyl)piperidin-1-yl]-4-oxo-N-(tricyclo MS (ESpos): m/z =549.5 [M + H]⁺ [3.3.1.1^(3,7)]dec-1-yl)-1,4-dihydro-1,8- ¹H-NMR (400MHz, DMSO-d₆) δ [ppm]: naphthyridine-3-carboxamide −0.150 (0.21), −0.009(1.84), 0.007 (1.70), 1.236 (0.37), 1.482 (0.76), 1.535 (0.66),

1.567 (0.70), 1.670 (7.53), 1.764 (0.57), 1.796 (0.50), 2.054 (16.00),2.072 (5.28), 2.365 (0.29), 2.709 (0.31), 2.797 (0.25), 3.502 (0.84),4.064 (0.44), 4.098 (0.42), 4.216 (0.54), 4.660 (0.70), 7.023 (1.61),7.046 (1.69), 7.290 (0.40), 7.312 (0.79), 7.332 (0.44), 7.538 (0.42),7.564 (0.41), 7.751 (0.44), 7.773 (0.89), 7.788 (0.89), 7.810 (0.43),8.207 (2.03), 8.230 (1.91), 8.457 (4.04), 9.953 (2.51). (30% of theory)16 1-(2,4-Difluorophenyl)-7-[4-fluoro-4-(hydroxy- LC-MS (Method 1):R_(t) = 1.28 min methyl)piperidin-1-yl]-4-oxo-N-(tricyclo MS (ESpos):m/z = 567.4 [M + H]⁺ [3.3.1.1^(3,7)]dec-1-yl)-1,4-dihydro-1,8- ¹H-NMR(500 MHz, DMSO-d₆) δ [ppm]: naphthyridine-3-carboxamide −0.004 (1.82),1.158 (0.27), 1.172 (0.55), 1.187 (0.28), 1.226 (0.04), 1.493 (0.22),

1.517 (0.43), 1.538 (0.34), 1.588 (0.43), 1.608 (0.33), 1.666 (7.42),1.921 (0.06), 1.986 (1.03), 2.052 (16.00), 2.180 (0.05), 3.171 (0.46),3.357 (1.33), 3.369 (1.34), 3.397 (1.31), 3.408 (1.34), 3.968 (0.84),3.989 (0.79), 4.020 (0.26), 4.034 (0.24), 4.049 (0.08), 4.942 (0.95),4.954 (2.16), 4.965 (0.91), 7.113 (1.93), 7.131 (1.95), 7.305 (0.40),7.309 (0.43), 7.322 (0.78), 7.326 (0.80), 7.339 (0.43), 7.343 (0.43),7.552 (0.50), 7.558 (0.53), 7.573 (0.76), 7.576 (0.77), 7.591 (0.51),7.596 (0.49), 7.771 (0.48), 7.783 (0.58), 7.788 (0.95), 7.800 (0.94),7.806 (0.54), 7.818 (0.45), 8.266 (2.80), 8.284 (2.54), 8.492 (5.72),9.913 (2.79). (85% of theory) 17 1-(2,4-Difluorophenyl)-7-[3-(2-hydroxy-LC-MS (Method 1): R_(t) = 1.27 minethyl)piperidin-1-yl]-4-oxo-N-(tricyclo MS (ESpos): m/z = 563.3 [M + H]⁺[3.3.1.1^(3,7)]dec-1-yl)-1,4-dihydro-1,8- ¹H-NMR (400 MHz, DMSO-d₆) δ[ppm]: naphthyridine-3-carboxamide −0.009 (0.83), 0.007 (0.78), 0.935(3.19), 0.951 (2.99), 1.145 (0.47), 1.172 (0.53),

1.242 (1.02), 1.258 (1.12), 1.447 (0.35), 1.583 (0.44), 1.669 (7.61),1.741 (0.45), 1.881 (0.30), 1.901 (0.37), 1.920 (0.32), 1.937 (0.14),2.053 (16.00), 2.155 (0.33), 2.176 (0.46), 2.195 (0.25), 2.327 (0.13),2.366 (0.20), 2.409 (0.36), 2.426 (0.36), 2.669 (0.16), 2.694 (1.84),2.709 (0.23), 2.944 (0.40), 2.960 (0.40), 3.284 (0.93), 4.019 (0.87),4.346 (0.46), 4.359 (0.56), 7.043 (1.77), 7.067 (1.81), 7.298 (0.38),7.320 (0.75), 7.340 (0.41), 7.549 (0.51), 7.568 (0.52), 7.756 (0.47),7.771 (0.56), 7.778 (0.91), 7.793 (0.91), 7.799 (0.53), 7.814 (0.44),8.224 (2.04), 8.246 (1.89), 8.463 (3.15), 9.938 (2.76). Workup: addwater and then 1 M aq. hydrochloric acid. The precipitate formed wasfiltered off. (86% of theory) 181-(2,4-Difluorophenyl)-4-oxo-7-(3-oxopiperazin- LC-MS (Method 1): R_(t)= 1.11 min 1-yl)-N-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)- MS (ESpos): m/z =534.4 [M + H]⁺ 1,4-dihydro-1,8-naphthyridine-3-carboxamide ¹H-NMR (400MHz, DMSO-d₆) δ [ppm]: −0.013 (0.90), 0.003 (0.81), 0.915 (0.58),

0.930 (4.33), 0.946 (4.10), 1.666 (7.41), 1.877 (0.19), 1.897 (0.25),1.915 (0.21), 2.052 (16.00), 2.151 (0.23), 2.171 (0.30), 2.191 (0.17),2.322 (0.13), 2.361 (0.17), 2.386 (0.18), 2.404 (0.48), 2.421 (0.47),2.439 (0.17), 2.664 (0.14), 2.689 (1.26), 2.705 (0.18), 2.939 (0.26),2.955 (0.35), 2.972 (0.26), 3.219 (1.44), 3.280 (0.50), 3.631 (1.43),3.896 (2.24), 7.041 (1.72), 7.064 (1.76), 7.315 (0.41), 7.337 (0.79),7.358 (0.44), 7.562 (0.50), 7.569 (0.52), 7.591 (0.74), 7.610 (0.52),7.617 (0.50), 7.773 (0.50), 7.788 (0.58), 7.794 (0.96), 7.809 (0.96),7.816 (0.54), 7.831 (0.47), 8.138 (1.26), 8.309 (2.58), 8.332 (2.40),8.503 (4.84), 9.886 (2.76). (96% of theory)

Example 191-(2,4-Difluorophenyl)-7-[(3R)-3-methoxypyrrolidin-1-yl]-N-(4-methylbicyclo[2.2.2]oct-1-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide

A mixture of 100 mg (0.18 mmol) of the compound from Example 70A, 50 mg(0.23 mmol) of (3R)-3-methoxypyrrolidine trifluoroacetate and 114 mg(0.89 mmol) of DIPEA in 3.6 ml of NMP was stirred at 23° C. for 24 h.Subsequently, the mixture was purified via preparative HPLC (Method 7).This gave 61 mg (66% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.38 min; m/z=523.3 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.150 (0.80), −0.009 (7.08), 0.007(6.82), 0.146 (0.80), 0.786 (16.00), 0.824 (0.73), 0.947 (0.63), 0.965(0.63), 1.147 (0.53), 1.156 (0.75), 1.174 (1.49), 1.192 (0.80), 1.235(0.53), 1.447 (4.65), 1.467 (6.04), 1.487 (5.65), 1.893 (5.84), 1.906(5.88), 1.914 (6.31), 1.933 (5.14), 1.987 (2.90), 2.327 (1.20), 2.366(2.84), 2.520 (3.49), 2.523 (3.78), 2.525 (3.98), 2.559 (1.63), 2.562(1.22), 2.569 (0.71), 2.573 (0.55), 2.664 (0.98), 2.669 (1.27), 2.673(0.90), 2.709 (2.86), 3.203 (3.51), 3.369 (0.53), 3.510 (0.75), 4.020(0.69), 4.038 (0.75), 4.056 (0.53), 6.713 (4.24), 6.735 (4.29), 7.290(0.65), 7.309 (1.27), 7.335 (0.75), 7.559 (0.86), 7.747 (0.67), 7.769(1.33), 7.784 (1.31), 7.805 (0.55), 8.246 (3.49), 8.268 (3.25), 8.465(8.24), 9.893 (4.82).

In analogy to Example 19, the example compounds shown in Table 2 wereprepared by reacting the compound from Example 70A with(R)-(−)-3-hydroxypyrrolidine hydrochloride.

TABLE 2 Ex. Analytical data 20 1-(2,4-Difluorophenyl)-7-[(3R)-3-hydroxy-LC-MS (Method 1): R_(t) = 1.21 min pyrrolidin-1-yl]-N-(4-methylbicycloMS (ESpos): m/z = 509.3 [M + H]⁺ [2.2.2]oct-1-yl)-4-oxo-1,4-dihydro-1,8-¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: naphthyridine-3-carboxamide −0.150(0.42), 0.146 (0.38), 0.786 (12.69), 1.156 (4.38), 1.174 (8.48), 1.192(4.27),

1.448 (4.66), 1.467 (6.21), 1.487 (5.27), 1.782 (0.40), 1.893 (6.18),1.914 (6.62), 1.933 (4.80), 1.987 (16.00), 2.327 (0.72), 2.366 (0.96),2.669 (0.74), 2.710 (1.01), 3.054 (0.40), 3.149 (0.75), 3.498 (0.91),4.002 (1.32), 4.020 (3.89), 4.038 (3.86), 4.056 (1.25), 4.248 (0.53),4.370 (0.46), 4.894 (0.37), 4.954 (0.34), 5.007 (0.35), 6.707 (1.01),7.288 (0.71), 7.309 (1.31), 7.328 (0.77), 7.538 (0.71), 7.560 (1.28),7.579 (0.66), 7.745 (0.53), 7.765 (1.05), 7.780 (1.03), 7.802 (0.51),8.237 (1.63), 8.259 (1.67), 8.458 (5.07), 9.902 (4.00). (69% of theory)

Example 211-(2,4-Difluorophenyl)-N-[2-(2,6-difluorophenyl)propan-2-yl]-7-[(3R)-3-hydroxypyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide

A mixture of 400 mg (0.61 mmol) of the compound from Example 71A, 151 mg(1.2 mmol) of (R)-(−)-3-hydroxypyrrolidine hydrochloride and 396 mg (3.0mmol) of DIPEA in 12.5 ml of NMP was stirred at 23° C. for 24 h.Subsequently, the mixture was concentrated under reduced pressure andpurified via preparative HPLC (Method 7). This gave 201 mg (59% oftheory) of the title compound.

LC-MS (Method 1): R_(t)=1.10 min; m/z=541.3 [M+H]⁺.

1H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.009 (2.16), −0.007 (1.87), 0.007(2.12), 1.156 (3.27), 1.174 (6.61), 1.192 (3.31), 1.824 (16.00), 1.899(0.99), 1.987 (12.10), 2.327 (0.40), 2.366 (0.62), 2.520 (1.01), 2.523(1.08), 2.525 (1.05), 2.558 (0.48), 2.560 (0.39), 2.563 (0.35), 2.665(0.32), 2.669 (0.41), 2.673 (0.33), 2.709 (0.62), 3.047 (0.34), 3.154(0.68), 3.507 (0.82), 4.002 (0.92), 4.020 (2.74), 4.038 (2.73), 4.055(0.88), 4.252 (0.52), 4.379 (0.44), 4.892 (0.29), 4.953 (0.32), 5.007(0.29), 6.733 (0.92), 6.756 (0.59), 6.923 (0.37), 6.935 (2.26), 6.957(3.14), 6.982 (2.65), 6.995 (0.39), 7.226 (0.48), 7.241 (1.09), 7.247(1.04), 7.262 (2.30), 7.277 (2.05), 7.283 (2.06), 7.298 (1.07), 7.510(0.64), 7.515 (0.68), 7.537 (1.19), 7.557 (0.67), 7.563 (0.64), 7.730(0.45), 7.751 (0.96), 7.767 (0.93), 7.788 (0.41), 8.148 (0.29), 8.274(1.68), 8.297 (1.63), 8.398 (6.56), 10.700 (4.58).

In analogy to Example 21, the example compounds shown in Table 3 wereprepared by reacting the compound from Example 71A with(3R)-3-methoxypyrrolidine trifluoroacetate.

TABLE 3 Ex. Analytical data 221-(2,4-Difluorophenyl)-N-[2-(2,6-difluoro- LC-MS (Method 1): R_(t) =1.19 min phenyl)propan-2-yl]-7-[(3R)-3-methoxypyrrolidin- MS (ESpos):m/z = 541.3 [M + H]⁺ 1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine- ¹H-NMR(400 MHz, DMSO-d₆) δ [ppm]: 3-carboxamide −0.009 (1.27), 0.007 (1.11),1.156 (4.13), 1.174 (8.37), 1.192 (4.22), 1.824 (11.59), 1.907 (1.33),

1.936 (1.03), 1.987 (16.00), 3.205 (2.05), 3.444 (0.43), 3.526 (0.53),3.573 (0.41), 4.002 (1.30), 4.020 (3.76), 4.038 (3.78), 4.055 (1.40),6.739 (2.53), 6.761 (2.58), 6.935 (1.64), 6.957 (2.30), 6.982 (1.93),7.242 (0.81), 7.248 (0.82), 7.262 (1.61), 7.278 (1.49), 7.283 (1.44),7.299 (0.73), 7.515 (0.40), 7.538 (0.66), 7.555 (0.46), 7.733 (0.43),7.755 (0.85), 7.770 (0.86), 8.284 (2.18), 8.306 (2.06), 8.379 (0.40),8.406 (5.65), 8.426 (0.41), 10.691 (3.02). (80% of theory)

Example 23 rac-Methyl4-{8-(2,4-difluorophenyl)-5-oxo-6-[(1,1,1-trifluorobutan-2-yl)carbamoyl]-5,8-dihydro-1,8-naphthyridin-2-yl}piperazine-1-carboxylate

A mixture of 100 mg (0.2 mmol) of the compound from Example 66A, 65 mg(0.45 mmol) of methyl piperazine-1-carboxylate and 116 mg (0.9 mmol) ofDIPEA in 4.6 ml of NMP was stirred at 23° C. for 24 h. The mixture wasthen diluted with water and brought to pH 7 with 1 M aqueoushydrochloric acid, and the precipitated solid was filtered off. Thesolid obtained was washed with water and petroleum ether. This gave 98mg (76% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.11 min; m/z=554.2 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.009 (2.77), 0.007 (2.54), 0.946(2.28), 0.964 (5.05), 0.983 (2.47), 1.156 (1.15), 1.174 (2.29), 1.192(1.16), 1.615 (0.44), 1.632 (0.54), 1.641 (0.48), 1.650 (0.45), 1.658(0.53), 1.859 (0.47), 1.868 (0.46), 1.878 (0.54), 1.884 (0.47), 1.894(0.42), 1.987 (4.10), 2.523 (0.64), 3.381 (3.36), 3.394 (2.76), 3.508(2.37), 3.519 (3.03), 3.594 (1.16), 3.604 (16.00), 4.020 (0.95), 4.038(0.96), 4.734 (0.46), 4.754 (0.43), 7.108 (2.25), 7.131 (2.32), 7.312(0.43), 7.329 (0.82), 7.334 (0.85), 7.350 (0.46), 7.355 (0.46), 7.560(0.51), 7.567 (0.54), 7.586 (0.80), 7.589 (0.80), 7.609 (0.54), 7.616(0.52), 7.801 (0.54), 7.811 (0.55), 7.825 (0.53), 8.321 (3.02), 8.344(2.79), 8.641 (1.92), 8.647 (1.77), 10.431 (1.61), 10.455 (1.56). 660 mgof the racemic title compound were separated into the enantiomers bychiral HPLC (preparative HPLC: column: Daicel® Chiralpak AD-H, 5 m,250×20 mm; eluent: 85% CO₂/15% isopropanol; flow rate 70 ml/min; 40° C.,detection: 210 nm).

This gave (in the sequence of elution from the column) 252 mg ofenantiomer A R_(t)=2.24 min and 230 mg of enantiomer B R_(t)=2.51 min.

[Analytical HPLC: column: SFC Daicel® Chiralpak AD-3, 3 ml/min; eluentA: CO₂, eluent B: isopropanol, gradient 5% B→50% B]

Example 24 ent-Methyl4-{8-(2,4-difluorophenyl)-5-oxo-6-[(1,1,1-trifluorobutan-2-yl)carbamoyl]-5,8-dihydro-1,8-naphthyridin-2-yl}piperazine-1-carboxylate(Enantiomer A) Example 25 ent-Methyl4-{8-(2,4-difluorophenyl)-5-oxo-6-[(1,1,1-trifluorobutan-2-yl)carbamoyl]-5,8-dihydro-1,8-naphthyridin-2-yl}piperazine-1-carboxylate(Enantiomer B)

In analogy to Example 23, the example compounds shown in Table 4 wereprepared by reacting the compound from Example 66A or 67A with theappropriate amines (or salts thereof) under the reaction conditionsdescribed. Differences are specified in the respective examples.

TABLE 4 Ex. Analytical data 26 rac-1-(2,4-Difluorophenyl)-7-[3-(hydroxy-LC-MS (Method 1): R_(t) = 0.98 min methyl)azetidin-1-yl]-4-oxo-N-[1,1,1-MS (ESpos): m/z = 497.2 [M + H]⁺ trifluorobutan-2-yl]-1,4-dihydro-1,8-¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: naphthyridine-3-carboxamide −0.009(2.48), 0.007 (2.54), 0.943 (7.17), 0.961 (16.00), 0.979 (7.83), 1.156(2.16), 1.174

(4.31), 1.192 (2.20), 1.592 (1.08), 1.610 (1.44), 1.617 (1.31), 1.627(1.76), 1.635 (1.60), 1.645 (1.56), 1.652 (1.71), 1.671 (1.29), 1.845(1.29), 1.855 (1.50), 1.864 (1.51), 1.873 (1.71), 1.880 (1.53), 1.890(1.34), 1.899 (1.16), 1.908 (1.03), 1.987 (7.76), 2.709 (0.66), 2.722(0.66), 2.736 (1.22), 2.742 (1.47), 2.756 (2.11), 2.770 (1.55), 2.776(1.32), 2.791 (0.75), 3.499 (5.39), 3.513 (9.07), 3.527 (5.29), 3.777(0.78), 4.002 (1.02), 4.020 (2.25), 4.037 (2.22), 4.055 (0.99), 4.703(0.79), 4.718 (1.35), 4.726 (1.43), 4.747 (1.44), 4.764 (3.32), 4.777(5.94), 4.790 (2.69), 6.559 (9.51), 6.581 (9.58), 7.280 (1.33), 7.284(1.45), 7.287 (1.39), 7.301 (2.68), 7.306 (2.81), 7.322 (1.50), 7.327(1.54), 7.329 (80% of theory) (1.42), 7.524 (1.63), 7.530 (1.72), 7.549(2.56), 7.553 (2.59), 7.572 (1.72), 7.579 (1.66), 7.761 (0.88), 7.782(1.90), 7.798 (1.86), 7.818 (0.79), 8.254 (9.96), 8.276 (9.63), 8.593(10.07), 10.486 (5.14), 10.510 (4.93). 271-(2,4-Difluorophenyl)-7-[(2-fluoro- LC-MS (Method 1): R_(t) = 1.08 minethyl)amino]-4-oxo-N-[(2R)-1,1,1-trifluorobutan- MS (ESpos): m/z = 473.3[M + H]⁺ 2-yl]-1,4-dihydro-1,8-naphthyridine-3- ¹H-NMR (400 MHz,DMSO-d₆) δ [ppm]: carboxamide −0.010 (1.41), 0.943 (7.22), 0.961(16.00), 0.980 (7.84), 1.594 (1.08), 1.612 (1.45), 1.619

(1.30), 1.628 (1.78), 1.637 (1.59), 1.647 (1.52), 1.654 (1.72), 1.672(1.30), 1.846 (1.27), 1.856 (1.47), 1.864 (1.51), 1.875 (1.70), 1.881(1.52), 1.891 (1.34), 1.900 (1.15), 1.908 (1.18), 3.161 (5.33), 3.174(5.48), 3.241 (1.95), 4.075 (1.84), 4.088 (1.80), 4.248 (2.71), 4.366(2.71), 4.727 (1.47), 4.743 (1.38), 6.728 (4.34), 6.750 (4.47), 7.298(1.44), 7.319 (2.88), 7.336 (1.53), 7.340 (1.58), 7.539 (1.60), 7.546(1.68), 7.565 (2.66), 7.568 (2.69), 7.587 (1.71), 7.594 (1.66), 7.805(1.94), 7.813 (1.70), 7.827 (1.93), 8.199 (5.46), 8.221 (5.11), 8.602(5.92), 10.503 (4.35), 10.527 (4.24). Compound from Ex. 67A and2-fluoroethyl- amine hydrochloride (28% of theory) 287-(6,6-Difluoro-3-azabicyclo[3.1.0]hex-3- LC-MS (Method 1): R_(t) = 1.14min yl)-1-(2,4-difluorophenyl)-4-oxo-N-[(2R)- MS (ESpos): m/z = 529.2[M + H]⁺ 1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8- ¹H-NMR (400 MHz,DMSO-d₆) δ [ppm]: naphthyridine-3-carboxamide −0.009 (5.85), 0.007(5.33), 0.946 (5.73), 0.965 (12.67), 0.983 (6.30), 1.156 (4.25), 1.174

(8.61), 1.192 (4.36), 1.615 (1.09), 1.623 (0.95), 1.632 (1.35), 1.641(1.24), 1.650 (1.18), 1.658 (1.35), 1.676 (0.99), 1.849 (1.00), 1.858(1.19), 1.867 (1.21), 1.877 (1.36), 1.884 (1.23), 1.894 (1.09), 1.987(16.00), 2.365 (1.97), 2.519 (3.11), 2.522 (3.24), 2.561 (1.42), 2.563(1.28), 2.623 (1.10), 2.669 (1.19), 2.709 (2.96), 2.730 (1.03), 3.438(1.56), 3.818 (2.15), 4.002 (1.31), 4.020 (3.85), 4.038 (3.83), 4.055(1.28), 4.733 (1.15), 4.747 (1.10), 6.772 (5.99), 6.794 (6.14), 7.309(1.00), 7.329 (1.92), 7.346 (1.08), 7.581 (1.05), 7.815 (1.42), 7.831(1.36), 8.318 (6.82), 8.340 (6.51), 8.638 (6.35), 10.443 (3.83), 10.467(3.73). Compound from Ex. 67A and 6,6-difluoro-3-azabicyclo[3.1.0]hexane hydrochloride (81% of theory) 297-(1,1-Difluoro-5-azaspiro[2.4]hept-5-yl)-1- LC-MS (Method 1): R_(t) =1.23 min (2,4-difluorophenyl)-4-oxo-N-[(2R)-1,1,1- MS (ESpos): m/z =543.2 [M + H]⁺ trifluorobutan-2-yl]-1,4-dihydro-1,8- ¹H-NMR (400 MHz,DMSO-d₆) δ [ppm]: naphthyridine-3-carboxamide (diastereomer mixture)−0.150 (2.00), 0.007 (16.00), 0.146 (1.96), 0.948 (5.32), 0.967 (10.79),0.986 (5.25),

1.156 (3.44), 1.174 (6.39), 1.192 (3.21), 1.237 (0.78), 1.618 (3.03),1.634 (2.73), 1.860 (1.18), 1.870 (1.26), 1.879 (1.29), 1.896 (1.18),1.987 (12.34), 2.127 (0.96), 2.327 (1.74), 2.366 (6.87), 2.671 (1.81),2.710 (6.54), 3.599 (0.92), 4.002 (1.18), 4.020 (2.85), 4.038 (2.85),4.055 (0.92), 4.735 (1.22), 6.783 (1.18), 7.297 (1.22), 7.316 (2.11),7.333 (1.18), 7.539 (1.07), 7.558 (1.81), 7.580 (0.96), 7.805 (1.55),7.819 (1.59), 8.315 (3.92), 8.338 (3.77), 8.629 (5.54), 10.468 (3.21),10.492 (3.07). Compound from Ex. 67A and 1,1-difluoro-5-azaspiro[2.4]heptane hydrochloride (74% of theory) 301-(2,4-Difluorophenyl)-7-(3-fluoro-3- LC-MS (Method 1): R_(t) = 1.26 minmethylpyrrolidin-1-yl)-4-oxo-N-[(2R)-1,1,1- MS (ESpos): m/z = 513.3 [M +H]⁺ trifluorobutan-2-yl]-1,4-dihydro-1,8- ¹H-NMR (400 MHz, DMSO-d₆) δ[ppm]: naphthyridine-3-carboxamide (diastereomer −0.002 (16.00), 0.948(5.01), 0.967 (11.10), mixture) 0.985 (5.46), 1.156 (1.21), 1.173(2.44), 1.191 (1.23), 1.459 (1.19), 1.511 (2.33), 1.565

(1.27), 1.599 (0.91), 1.617 (1.07), 1.624 (0.94), 1.633 (1.24), 1.642(1.13), 1.652 (1.06), 1.659 (1.21), 1.677 (0.91), 1.695 (0.26), 1.850(0.89), 1.860 (1.04), 1.868 (1.07), 1.878 (1.19), 1.885 (1.05), 1.895(0.94), 1.903 (0.82), 1.913 (0.70), 1.987 (4.81), 2.137 (0.61), 2.366(0.59), 2.709 (0.59), 3.166 (7.39), 3.532 (0.58), 3.699 (0.58), 4.001(0.41), 4.019 (1.16), 4.037 (1.20), 4.055 (0.66), 4.077 (1.28), 4.089(1.19), 4.733 (1.03), 4.752 (0.97), 6.755 (0.65), 6.797 (0.60), 7.305(0.82), 7.325 (1.62), 7.343 (0.96), 7.575 (1.25), 7.595 (0.87), 7.810(1.27), 7.826 (1.24), 8.309 (1.63), 8.330 (1.59), 8.625 (5.70), 10.476(3.51), 10.500 (3.39). Compound from Ex. 67A and 3-fluoro-3-methylpyrrolidine para-toluenesulphonic acid salt (85% of theory) 311-(2,4-Difluorophenyl)-7-[(2R,4S)-4-fluoro- LC-MS (Method 1): R_(t) =1.27 min 2-methylpyrrolidin-1-yl]-4-oxo-N-[(2R)- MS (ESpos): m/z = 513.3[M + H]⁺ 1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8- ¹H-NMR (400 MHz,DMSO-d₆) δ [ppm]: naphthyridine-3-carboxamide −0.150 (0.90), −0.009(8.02), 0.007 (7.82), 0.145 (0.90), 0.891 (0.90), 0.949 (7.45), 0.968

(16.00), 0.986 (8.02), 1.047 (1.02), 1.133 (0.70), 1.146 (0.90), 1.156(0.94), 1.174 (1.51), 1.192 (0.98), 1.235 (0.57), 1.600 (1.06), 1.618(1.43), 1.625 (1.35), 1.635 (1.68), 1.643 (1.60), 1.653 (1.47), 1.660(1.72), 1.679 (1.35), 1.698 (0.37), 1.851 (1.35), 1.861 (1.51), 1.870(1.64), 1.880 (1.88), 1.886 (1.72), 1.896 (1.64), 1.904 (1.51), 1.914(1.43), 1.987 (2.58), 2.226 (0.53), 2.251 (0.53), 2.322 (1.15), 2.327(1.47), 2.331 (1.19), 2.347 (0.57), 2.365 (6.55), 2.454 (0.45), 2.518(6.51), 2.564 (2.25), 2.567 (2.13), 2.575 (1.15), 2.585 (0.65), 2.589(0.49), 2.594 (0.49), 2.596 (0.49), 2.611 (0.41), 2.665 (0.90), 2.669(1.19), 2.674 (0.86), 2.709 (6.38), 3.161 (2.46), 3.174 (2.70), 3.443(0.37), 3.456 Compound from Ex. 67A and (2R,4S)-4- (0.49), 3.820 (0.53),3.916 (0.53), 4.002 fluoro-2-methylpyrrolidine para-toluene- (0.41),4.020 (0.57), 4.038 (0.61), 4.061 sulphonic acid salt (0.37), 4.074(0.70), 4.087 (0.70), 4.712 (70% of theory) (0.82), 4.735 (1.39), 4.754(1.35), 5.331 (0.70), 5.462 (0.70), 6.759 (0.82), 7.307 (1.27), 7.328(2.58), 7.348 (1.43), 7.574 (1.47), 7.591 (1.64), 7.792 (1.15), 7.813(2.33), 7.829 (2.25), 7.850 (1.06), 8.306 (7.53), 8.328 (7.12), 8.644(9.49), 10.479 (5.07), 10.503 (4.87). 321-(2,4-Difluorophenyl)-7-(3-fluoroazetidin- LC-MS (Method 1): R_(t) =1.19 min 1-yl)-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2- MS (ESpos): m/z =485.3 [M + H]⁺ yl]-1,4-dihydro-1,8-naphthyridine-3-carbox- ¹H-NMR (400MHz, DMSO-d₆) δ [ppm]: amide −0.013 (4.92), 0.003 (4.10), 0.851 (3.11),0.869 (6.83), 0.887 (3.72), 0.940 (7.25), 0.959

(16.00), 0.977 (7.76), 1.083 (1.53), 1.103 (2.06), 1.123 (1.81), 1.276(1.29), 1.295 (2.23), 1.313 (2.25), 1.573 (1.82), 1.592 (2.84), 1.611(2.42), 1.628 (1.99), 1.636 (1.74), 1.646 (1.61), 1.653 (1.84), 1.671(1.50), 1.844 (1.34), 1.854 (1.55), 1.863 (1.53), 1.872 (1.73), 1.879(1.53), 1.889 (1.38), 1.983 (1.34), 4.016 (1.51), 4.033 (1.42), 4.260(1.47), 4.728 (1.44), 4.748 (1.39), 5.365 (1.42), 5.372 (1.67), 5.379(1.36), 5.508 (1.35), 5.515 (1.72), 5.522 (1.36), 6.654 (9.23), 6.676(9.40), 7.289 (1.50), 7.306 (2.80), 7.311 (2.88), 7.328 (1.57), 7.332(1.64), 7.527 (1.81), 7.534 (1.84), 7.553 (2.73), 7.556 (2.77), 7.576(1.81), 7.582 (1.71), 7.792 (2.02), 7.808 (1.97), 8.320 (9.70), 8.342(9.33), 8.629 Compound from Ex. 67A and 3-fluoroazetidine (10.09),10.427 (4.92), 10.450 (4.79). hydrochloride (37% of theory) 331-(2,4-Difluorophenyl)-7-[(3R,4R)-4-fluoro- LC-MS (Method 1): R_(t) =1.07 min 3-hydroxypiperidin-1-yl]-4-oxo-N-[(2R)- MS (ESpos): m/z = 529.3[M + H]⁺ 1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8- ¹H-NMR (500 MHz,DMSO-d₆) δ [ppm]: naphthyridine-3-carboxamide −0.005 (6.51), 0.949(7.71), 0.964 (16.00), 0.978 (7.85), 1.483 (1.21), 1.605 (1.14), 1.611

(0.61), 1.620 (1.52), 1.626 (1.37), 1.633 (1.76), 1.640 (1.60), 1.648(1.52), 1.654 (1.65), 1.668 (1.22), 1.840 (0.49), 1.855 (1.29), 1.862(1.50), 1.869 (1.53), 1.877 (1.72), 1.882 (1.56), 1.890 (1.39), 1.897(1.19), 1.905 (1.04), 1.977 (1.18), 1.986 (1.37), 3.044 (0.64), 3.172(1.08), 3.180 (1.05), 3.207 (0.72), 3.216 (0.73), 3.242 (1.01), 3.262(0.72), 3.458 (1.12), 3.800 (0.90), 3.879 (0.84), 3.910 (1.36), 3.940(0.77), 4.427 (0.95), 4.525 (0.97), 4.733 (1.48), 4.745 (1.40), 4.761(0.80), 5.444 (1.68), 5.454 (2.00), 5.463 (2.46), 5.473 (2.06), 7.144(6.66), 7.162 (6.72), 7.314 (1.45), 7.331 (2.76), 7.345 (1.54), 7.539(0.72), 7.561 (1.54), 7.582 (1.53), 7.602 (0.74), 7.811 (1.41), 7.822(1.95), 7.834 Compound from Ex. 67A and (4R)-fluoro- (1.51), 8.289(3.51), 8.293 (3.42), 8.307 (3R)-piperidinol (HCl salt) (3.42), 8.311(3.20), 8.636 (6.64), 10.447 (75% of theory) (4.07), 10.466 (3.95). 341-(2,4-Difluorophenyl)-7-[3-fluoro-4,4- LC-MS (Method 1): R_(t) = 0.95min dihydroxypiperidin-1-yl]-4-oxo-N-[(2R)- MS (ESpos): m/z = 545.4 [M +H]⁺ 1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8- ¹H NMR (400 MHz,DMSO-d₆) δ [ppm]: naphthyridine-3-carboxamide (diastereomer −0.150(1.60), −0.009 (15.46), 0.007 (13.56), mixture) 0.146 (1.68), 0.824(0.88), 0.841 (2.18), 0.857 (3.04), 0.875 (1.57), 0.946 (7.18), 0.964

(16.00), 0.982 (8.24), 1.052 (0.41), 1.073 (0.52), 1.146 (0.93), 1.235(1.42), 1.291 (1.44), 1.551 (1.16), 1.597 (1.83), 1.614 (2.50), 1.631(3.47), 1.641 (3.64), 1.649 (3.77), 1.658 (3.02), 1.675 (1.98), 1.849(1.38), 1.858 (1.98), 1.867 (2.13), 1.876 (2.22), 1.884 (2.29), 1.893(1.94), 1.911 (1.25), 1.919 (0.95), 2.327 (2.16), 2.366 (3.80), 2.406(1.08), 2.669 (2.24), 2.709 (3.13), 2.992 (0.58), 3.173 (8.88), 3.935(0.80), 4.055 (0.71), 4.087 (0.73), 4.151 (0.60), 4.277 (1.90), 4.387(0.67), 4.466 (0.56), 4.563 (0.97), 4.745 (1.94), 4.930 (0.37), 5.041(0.39), 5.960 (1.49), 5.974 (1.79), 6.061 (1.51), 6.271 (1.01), 6.322(1.08), 7.144 (2.37), 7.155 (2.05), 7.167 (2.67), 7.179 (2.05), 7.320(1.81), 7.341 Compound from Ex. 67A and rac. 3-fluoro- (3.47), 7.355(3.82), 7.378 (2.54), 7.394 piperidin-4-one hydrochloride. Purificationby (1.83), 7.468 (0.37), 7.565 (1.55), 7.590 Preparative HPLC (eluent:acetonitrile/water (3.13), 7.613 (2.18), 7.817 (2.11), 7.830 gradientwith 0.1% formic acid). (2.35), 7.853 (1.90), 8.271 (2.74), 8.281 (10%of theory) (2.72), 8.294 (2.85), 8.303 (2.46), 8.406 (5.13), 8.428(4.72), 8.630 (5.80), 8.708 (2.98), 8.715 (3.39), 10.386 (2.67), 10.409(2.46), 10.443 (2.44), 10.451 (2.31), 10.468 (2.50). 357-(3,3-Difluoro-4,4-dihydroxypiperidin-1- LC-MS (Method 1): R_(t) = 0.97min yl)-1-(2,4-difluorophenyl)-4-oxo-N-[(2R)- MS (ESpos): m/z = 563.4[M + H]⁺ 1,1,1-trifluorobutran-2-yl]-1,4-dihydro-1,8- ¹H-NMR (400 MHz,DMSO-d₆) δ [ppm]: naphthyridine-3-carboxamide −0.009 (3.57), 0.007(3.08), 0.878 (1.06), 0.897 (2.32), 0.915 (1.20), 0.946 (7.02), 0.964

(15.55), 0.983 (7.62), 1.156 (3.54), 1.174 (7.22), 1.191 (3.64), 1.599(1.09), 1.617 (1.49), 1.624 (1.38), 1.634 (1.87), 1.643 (1.90), 1.652(2.23), 1.660 (3.02), 1.677 (3.45), 1.719 (1.10), 1.725 (1.09), 1.735(1.10), 1.743 (1.04), 1.753 (0.94), 1.851 (1.22), 1.860 (1.42), 1.869(1.41), 1.879 (1.61), 1.885 (1.45), 1.896 (1.25), 1.904 (1.15), 1.914(0.91), 1.987 (13.10), 2.523 (1.19), 3.243 (14.94), 3.563 (2.61), 3.842(1.83), 4.001 (1.06), 4.019 (3.06), 4.037 (3.03), 4.055 (1.02), 4.736(1.36), 4.751 (1.28), 5.752 (2.70), 6.432 (16.00), 6.787 (5.50), 7.238(2.48), 7.253 (2.10), 7.261 (2.70), 7.275 (1.77), 7.329 (1.38), 7.350(2.70), 7.366 (1.42), 7.371 (1.44), 7.574 (1.36), 7.580 (1.33), 7.599(2.36), 7.622 Compound from Ex. 67A and 3,3-difluoro- (1.39), 7.628(1.22), 7.818 (1.57), 7.830 piperidin-4-one hydrochloride, purified via(1.84), 7.842 (1.61), 8.320 (5.05), 8.330 preparative HPLC (eluent:acetonitrile/water (3.54), 8.343 (4.70), 8.353 (3.13), 8.658 gradientwith 0.1% formic acid. (4.55), 8.661 (4.61), 8.665 (4.83), 10.399 (62%of theory) (2.31), 10.408 (3.19), 10.424 (2.26), 10.432 (2.93).

Example 361-(2,4-Difluorophenyl)-7-(dimethylamino)-4-oxo-N-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

80 mg (0.23 mmol) of the compound from example 36A were initiallycharged in 2.3 ml of DMF, 106 mg (0.28 mmol) of HATU and 99 mg (0.77mmol) of DIPEA were added, and the mixture was stirred at 20° C. for 30minutes. Then 49 mg (0.32 mmol) of 1-adamantanamine were added and themixture was stirred at 20° C. for 2 hours. Subsequently, the mixture waspurified via preparative HPLC (eluent: acetonitrile/water gradient with0.1% formic acid). This gave 63 mg (57% of theory) of the titlecompound.

LC-MS (Method 1): R_(t)=1.34 min; m/z=479 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.008 (2.42), 0.009 (2.27), 1.671(7.70), 2.054 (16.00), 2.076 (1.22), 2.936 (2.35), 6.892 (2.41), 6.915(2.39), 7.304 (0.41), 7.319 (0.71), 7.327 (0.84), 7.340 (0.41), 7.346(0.47), 7.350 (0.41), 7.554 (0.53), 7.560 (0.54), 7.575 (0.69), 7.580(0.79), 7.586 (0.68), 7.602 (0.55), 7.609 (0.52), 7.767 (0.50), 7.781(0.59), 7.789 (1.00), 7.803 (0.99), 7.810 (0.55), 7.825 (0.46), 8.251(2.69), 8.275 (2.54), 8.477 (5.26), 9.952 (2.61).

In analogy to Example 36, the example compounds shown in Table 5 wereprepared by reacting the compound from Example 36A or 60A with theappropriate amines (or salts thereof) under the reaction conditionsdescribed. Differences are specified in the respective examples.

TABLE 5 Ex. Analytical Data 371-(2,4-Difluorophenyl)-7-(dimethylamino)-N-(3-fluorotricyclo LC-MS(Method 1): R_(t) = 1.29 min[3.3.1.1^(3,7)]dec-1-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3- MS(ESpos): m/z = 497.3 [M + H]⁺ carboxamide ¹H-NMR (400 MHz, CDCl₃) δ[ppm]: 0.009 (6.24),

0.017 (0.22), 0.078 (0.31), 1.576 (16.00), 1.631 (0.21), 1.889 (0.30),1.944 (0.26), 2.015 (0.21), 2.053 (0.18), 2.083 (0.35), 2.137 (0.30),2.379 (0.60), 2.450 (0.15), 2.795 (0.16), 2.993 (1.92), 3.500 (0.66),6.656 (0.74), 6.679 (0.75), 7.007 (0.28), 7.022 (0.32), 7.028 (0.30),7.041 (0.32), 7.047 (0.28), 7.059 (0.15), 7.351 (0.15), 7.372 (0.19),7.386 (0.20), 7.394 (0.14), 7.409 (0.12), 7.529 (0.15), 8.407 (0.75),8.429 (0.73), 8.627 (1.17), 10.134 (0.34). (33% of theory) 381-(2,4-Difluorophenyl)-N-(3,5-difluorotricy-clo[3.3.1.1^(3,7)] LC-MS(Method 1): R_(t) = 1.16 mindec-1-yl)-7-(dimethylamino)-4-oxo-1,4-dihydro-1,8- MS (ESpos): m/z =515.3 [M + H]⁺ naphthyridine-3-carboxamide ¹H-NMR (400 MHz, DMSO-d₆) δ[ppm]: -0.009

(9.96), 0.007 (6.42), 1.803 (11.32), 1.899 (7.42), 2.072 (2.34), 2.138(3.86), 2.317 (4.06), 2.939 (8.32), 3.161 (10.82), 3.174 (10.98), 4.062(1.20), 4.075 (3.14), 4.088 (3.06), 6.902 (7.86), 6.925 (7.90), 7.303(1.50), 7.325 (2.64), 7.341 (1.46), 7.554 (1.88), 7.576 (2.60), 7.595(1.78), 7.766 (1.76), 7.788 (3.30), 7.803 (3.20), 7.825 (1.56), 8.256(8.82), 8.279 (8.28), 8.512 (16.00), 10.263 (7.66). (61% of theory) 391-(2,4-Difluorophenyl)-N-(4,4-difluorotricy- LC-MS (Method 1): R_(t) =1.26 min clo[3.3.1.1^(3,7)]dec-1-yl)-7-(dimethylamino)-4 MS (ESpos): m/z= 515.3 [M + H]⁺ oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide ¹H-NMR(400 MHz, DMSO-d₆) δ [ppm]: 1.785

(9.36), 2.065 (16.00), 2.277 (8.35), 2.362 (2.47), 2.932 (8.32), 6.892(5.42), 6.914 (5.67), 7.318 (2.44), 7.571 (2.32), 7.778 (2.38), 8.246(5.88), 8.269 (5.64), 8.483 (10.54), 10.042 (6.95). (28% of theory) 401-(2-Chloro-4-fluorophenyl)-N-(4,4- LC-MS (Method 1): Rt = 1.30 mindifluorotricyclo[3.3.1.1^(3,7)]dec-1-yl)-7-(dime- MS (ESpos): m/z =531.2 [M + H]⁺ thylamino)-4-oxo-1,4-dihydro-1,8-naphthy- ¹H-NMR (400MHz, DMSO-d₆) δ [ppm]: 1.790 ridine-3-carboxamide (8.79), 2.068 (16.00),2.280 (7.81), 2.366 (2.24),

2.709 (2.36), 2.906 (6.43), 6.882 (6.22), 6.905 (6.28), 7.473 (2.99),7.494 (1.91), 7.773 (4.13), 7.787 (4.64), 7.809 (2.78), 8.250 (6.52),8.272 (6.22), 8.410 (12.62), 10.064 (7.15). Compound from Ex. 60A (45%of theory) 41 1-(2,4-Difluorophenyl)-7-(dimethylamino)- LC-MS (Method1): R_(t) = 1.41 min N-(3-methyltricyclo[3.3.1.1^(3,7)]dec-1-yl)-4- MS(ESpos): m/z = 493.3 [M + H]⁺oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide ¹H-NMR (400 MHz,DMSO-d₆) δ [ppm]: 0.836

(16.00), 1.415 (9.74), 1.516 (1.11), 1.546 (1.92), 1.599 (1.99), 1.630(1.04), 1.761 (7.37), 1.912 (2.13), 1.940 (3.65), 1.999 (3.82), 2.027(2.14), 2.092 (4.16), 2.366 (0.43), 2.936 (6.28), 6.890 (3.74), 6.912(3.75), 7.302 (0.93), 7.318 (1.65), 7.339 (0.89), 7.553 (0.98), 7.572(1.58), 7.595 (0.96), 7.758 (0.93), 7.779 (1.71), 7.794 (1.68), 7.816(0.79), 8.247 (3.92), 8.269 (3.64), 8.467 (6.71), 9.958 (4.38). (67% oftheory) 42 1-(2,4-Difluorophenyl)-7-(dimethylamino)- LC-MS (Method 1):R_(t) = 1.38 min N-(4-methylbicyclo[2.2.2]oct-1-yl)-4-oxo- MS (ESpos):m/z = 467.3 [M + H]⁺ 1,4-dihydro-1,8-naphthyridine-3-carboxamide ¹H-NMR(400 MHz, DMSO-d₆) δ [ppm]: -0.014

(1.72), 0.003 (1.72), 0.781 (16.00), 1.442 (4.66), 1.461 (6.05), 1.481(5.60), 1.888 (5.60), 1.900 (5.04), 1.909 (5.99), 1.928 (4.77), 2.726(8.77), 2.885 (12.33), 2.928 (4.93), 6.879 (4.49), 6.902 (4.55), 7.285(0.67), 7.289 (0.74), 7.292 (0.70), 7.306 (1.37), 7.311 (1.42), 7.328(0.78), 7.332 (0.80), 7.335 (0.72), 7.534 (0.90), 7.541 (0.95), 7.560(1.32), 7.563 (1.35), 7.582 (0.94), 7.589 (0.92), 7.748 (0.89), 7.763(1.05), 7.769 (1.78), 7.784 (1.76), 7.791 (1.00), 7.806 (0.87), 7.947(1.22), 8.238 (4.90), 8.260 (4.64), 8.462 (8.75), 9.879 (4.75). (96% oftheory) 43 N-tery-Butyl-1-(2,4-difluorophenyl)-7-(dime- LC-MS (Method1): R_(t) = 1.12 min thylamino)-4-oxo-1,4-dihydro-1,8-naphthy- MS(ESpos): m/z = 401.1 [M + H]⁺ ridine-3-carboxamide ¹H-NMR (400 MHz,DMSO-d₆) δ [ppm]: -0.009

(0.52), 0.007 (0.34), 1.388 (16.00), 2.523 (0.72), 2.890 (0.41), 2.938(1.24), 6.894 (1.26), 6.916 (1.25), 7.317 (0.34), 7.321 (0.34), 7.552(0.25), 7.568 (0.32), 7.571 (0.33), 7.574 (0.33), 7.578 (0.29), 7.759(0.24), 7.774 (0.29), 7.780 (0.46), 7.795 (0.46), 7.802 (0.26), 8.253(1.33), 8.276 (1.27), 8.501 (2.21), 10.014 (1.06). (88% of theory) 441-(2,4-Difluorophenyl)-7-(dimethylamino)-4- LC-MS (Method 1): R_(t) =1.13 min oxo-N-[(2S)-1,1,1-trifluoropropan-2-yl]-1,4- MS (ESpos): m/z =441.1 [M + H]⁺ dihydro-1,8-naphthyridine-3-carboxamide ¹H-NMR (400 MHz,DMSO-d₆) δ [ppm]: -0.150

(1.10), -0.008 (11.13), 0.007 (9.84), 0.146 (1.10), 1.360 (15.85), 1.377(16.00), 2.365 (0.82), 2.709 (0.88), 2.945 (6.97), 4.860 (1.15), 4.880(1.78), 4.901 (1.81), 4.919 (1.13), 6.927 (7.86), 6.949 (8.04), 7.306(1.38), 7.326 (2.83), 7.348 (1.53), 7.558 (1.54), 7.580 (2.58), 7.599(1.57), 7.808 (1.47), 8.267 (8.65), 8.290 (8.27), 8.607 (6.53), 10.543(3.31), 10.566 (3.23). (35% of theory) 451-(2,4-Difluorophenyl)-7-(dimethylamino)-4- LC-MS (Method 1): R_(t) =1.21 min oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1,4- MS (ESpos): m/z =455.2 [M + H ]⁺ dihydro-1,8-naphthyridine-3-carboxamide ¹H-NMR (400 MHz,DMSO-d₆) δ [ppm]: -0.009

(4.23), 0.007 (4.21), 0.946 (7.18), 0.965 (16.00), 0.983 (7.72), 1.613(1.53), 1.630 (1.75), 1.639 (1.51), 1.648 (1.41), 1.655 (1.78), 1.858(1.43), 1.867 (1.52), 1.876 (1.65), 1.883 (1.44), 2.669 (1.34), 2.947(6.45), 4.732 (1.34), 4.747 (1.36), 6.929 (9.58), 6.952 (9.93), 7.304(1.41), 7.327 (2.80), 7.343 (1.55), 7.551 (1.78), 7.558 (1.87), 7.576(2.74), 7.599 (1.90), 7.606 (1.86), 7.805 (1.90), 7.827 (1.83), 8.275(11.06), 8.298 (10.59), 8.614(7.21), 10.490(4.78), 10.514(4.65). (74% oftheory) 46 rac-1-(2,4-Difluorophenyl)-7-(dimethyla- LC-MS (Method 1):R_(t) = 1.10 min mino)-4-oxo-N-[4,4,4-trifluorobutan-2-yl]- MS (ESpos):m/z = 455.3 [M + H]⁺ 1,4-dihydro-1,8-naphthyridine-3-carboxamide H-NMR(400 MHz, DMSO-d₆) δ [ppm]: 1.272

(15.86), 1.289 (15.96), 2.522 (1.97), 2.560 (2.34), 2.573 (1.89), 2.589(1.88), 2.602 (1.76), 2.653 (1.74), 2.672 (1.77), 2.939 (10.25), 4.357(1.92), 4.373 (2.32), 4.388 (1.85), 6.900 (7.38), 6.923 (7.55), 7.317(2.97), 7.322 (3.10), 7.343 (1.66), 7.546 (1.71), 7.553 (1.80), 7.572(2.88), 7.594 (1.79), 7.601 (1.69), 7.791 (2.15), 8.252 (8.40), 8.275(8.03), 8.534 (16.00), 10.126 (4.93), 10.147 (4.79). (82% of theory) 471-(2,4-Difluorophenyl)-7-(dimethylamino)- LC-MS (Method 1): R_(t) = 1.19rnin N-(4-fluorobicyclo [2.2.2]oct-1-yl)-4-oxo-1,4- MS (ESpos): m/z =471.3 [M + H]⁺ dihydro-1,8-naphthyridine-3-carboxamide ¹H-NMR (400 MHz,CDCl₃) δ [ppm]: 0.001 (0.16),

0.017 (0.15), 0.078 (0.09), 1.576 (16.00), 1.935 (0.16), 1.950 (0.30),1.965 (0.31), 1.976 (0.33), 1.990 (0.21), 2.235 (0.37), 2.247 (0.28),2.257 (0.35), 2.275 (0.28), 2.634 (0.10), 2.966 (0.08), 2.988 (0.82),6.651 (0.35), 6.674 (0.36), 7.006 (0.15), 7.022 (0.15), 7.027 (0.14),7.041 (0.15), 7.046 (0.12), 7.051 (0.09), 7.059 (0.07), 7.343 (0.07),7.357 (0.08), 7.364 (0.08), 7.377 (0.09), 8.392 (0.37), 8.415 (0.36),8.607 (0.58), 10.007 (0.15). (85% of theory) 48rac-N-[1-(2-Chlorophenyl)-2,2,2-trifluoro- LC-MS (Method 1): R_(t) =1.19 min ethyl]-1-(2,4-difluorophenyl)-7-(dimethyla- MS (ESpos): m/z =471.3 [M + H]⁺ mino)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: -0.013

(6.67), 0.003 (6.02), 2.322 (0.99), 2.361 (1.40), 2.664 (1.24), 2.705(1.56), 2.944 (4.69), 6.425 (1.75), 6.446 (2.37), 6.466 (1.61), 6.943(8.07), 6.966 (8.08), 7.306 (1.62), 7.325 (1.64), 7.471 (1.19), 7.475(1.31), 7.490 (3.28), 7.494 (3.47), 7.508 (3.26), 7.513 (3.29), 7.525(2.21), 7.544 (4.34), 7.561 (3.07), 7.594 (7.00), 7.598 (7.38), 7.613(5.54), 7.617 (4.99), 7.738 (0.97), 7.753 (0.91), 7.812 (0.95), 7.827(0.96), 8.312 (9.17), 8.335 (8.61), 8.620 (16.00), 11.614 (2.88), 11.637(2.62). (74% of theory) 49 N-(2,6-Dichlorobenzyl)-1-(2,4-difluoro- LC-MS(Method 1): R_(t) = 1.22 min phenyl)-7-(dimethylamino)-4-oxo-1,4-dihy-MS (ESpos): m/z = 503.0 [M + H]⁺ dro-1,8-naphthyridine-3-carboxamide¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 2.726

(3.73), 2.886 (6.85), 2.927 (11.71), 4.786 (4.36), 4.800 (4.64), 4.812(4.61), 4.825 (4.28), 6.879 (8.07), 6.902 (8.27), 7.315 (3.57), 7.374(3.40), 7.395 (6.06), 7.414 (5.77), 7.520 (16.00), 7.540 (12.58), 7.565(3.42), 7.773 (3.72), 7.788 (3.61), 8.217 (8.38), 8.240 (8.00), 8.565(14.86), 10.336 (2.96), 10.350 (5.68), 10.362 (2.79). (73% of theory) 50N-(2,4-Dmuorobenzyl)-1-(2,4-difluoro- LC-MS (Method 1): R_(t) = 1.15 minphenyl)-7-(dimethylamino)-4-oxo-1,4-dihy- MS (ESpos): m/z = 471.1 [M +H]⁺ dro-1,8-naphthyridine-3-carboxamide ¹H-NMR (400 MHz, DMSO-d₆) δ[ppm]: -0.009

(7.30), 0.007 (6.62), 2.939 (8.43), 4.558 (4.82), 4.567 (4.86), 6.898(7.29), 6.921 (7.44), 7.048 (1.32), 7.054 (1.43), 7.070 (2.82), 7.075(2.95), 7.091 (1.54), 7.097 (1.58), 7.218 (1.78), 7.225 (1.74), 7.243(2.60), 7.248 (2.50), 7.268 (1.90), 7.274 (1.76), 7.301 (1.33), 7.315(2.57), 7.321 (2.64), 7.336 (1.40), 7.341 (1.43), 7.413 (1.64), 7.435(3.27), 7.451 (3.31), 7.473 (1.48), 7.545 (1.64), 7.552 (1.70), 7.575(2.53), 7.594 (1.75), 7.601 (1.63), 7.756 (1.66), 7.771 (1.95), 7.778(3.29), 7.793 (3.27), 7.799 (1.86), 7.814 (1.57), 8.255 (8.00), 8.278(7.61), 8.555 (16.00), 10.346 (2.21), 10.361 (4.55), 10.376(2.15). (78%of theory) 51 1-(2,4-Difluorophenyl)-7-(dimethylamino)-N-(2,6-dimethylbenzyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide

LC-MS (Method 1): R_(t) = 1.22 rnin MS (ESpos): m/z = 463.2 [M + H]⁺¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: -0.013 (1.23), 0.003 (1.03), 2.068(0.40), 2.393 (16.00), 2.922 (1.87), 4.526 (0.91), 4.540 (1.40), 4.554(0.82), 6.869 (1.65), 6.892 (1.65), 7.043 (0.92), 7.060 (2.86), 7.084(1.56), 7.099 (0.78), 7.106 (0.56), 7.121 (0.34), 7.294 (0.32), 7.311(0.56), 7.337 (0.29), 7.540 (0.39), 7.547 (0.39), 7.566 (0.55), 7.588(0.37), 7.595 (0.35), 7.750 (0.38), 7.771 (0.70), 7.786 (0.69), 7.808(0.32), 8.198 (1.92), 8.221 (1.79), 8.564 (3.61), 10.077 (0.52), 10.090(0.94), 10.102 (0.43). (41% of theory) 521-(2,4-Difluorophenyl)-N-(2,6-difluoro- LC-MS (Method 1): R_(t) = 1.13min phenyl)-7-(dimethylamino)-4-oxo-1,4-dihy- MS (ESpos): m/z = 457.2[M + H]⁺ dro-1,8-naphthyridine-3-carboxamide ¹H-NMR (400 MHz, DMSO-d₆) δ[ppm]: -0.009

(2.92), 0.007 (2.64), 2.962 (5.97), 6.953 (7.45), 6.976 (7.64), 7.188(4.26), 7.209 (9.81), 7.229 (6.29), 7.328 (2.60), 7.336 (3.06), 7.354(3.59), 7.374 (3.14), 7.395 (1.60), 7.558 (1.60), 7.565 (1.68), 7.584(2.45), 7.588 (2.46), 7.607 (1.70), 7.614 (1.64), 7.808 (1.66), 7.823(1.94), 7.830 (3.26), 7.845 (3.24), 7.852 (1.81), 7.867 (1.58), 8.327(8.17), 8.350 (7.85), 8.690 (16.00), 11.813 (9.92). (62% of theory) 531-(2,4-Difluorophenyl)-N-[2-(2,6-difluoro- LC-MS (Method 1): R_(t) =1.22 min phenyl)propan-2-yl]-7-(dimethylamino)-4- MS (ESpos): m/z =499.2 [M + H]⁺ oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide ¹H-NMR(400 MHz, DMSO-d₆) δ [ppm]: -0.013

(8.59), 0.003 (7.77), 1.819 (16.00), 2.934 (4.18), 6.906 (4.62), 6.929(6.51), 6.953 (3.18), 6.977 (2.76), 7.257 (2.44), 7.278 (2.11), 7.539(1.48), 7.755 (1.87), 7.770 (1.85), 8.276 (5.32), 8.299 (4.95), 8.402(10.08), 10.676 (4.51). (100% of theory) 541-(2,4-Difluorophenyl)-7-(dimethylamino)-N-(2,6-dimethylphenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide

LC-MS (Method 1): R_(t) = 1.20 min MS (ESpos): m/z = 449.2 [M + H]+¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: -0.001 (3.96), 2.211 (16.00), 2.889(0.60), 2.962 (1.78), 6.939 (1.47), 6.962 (1.47), 7.114 (6.25), 7.321(0.66), 7.326 (0.65), 7.580 (0.61), 7.832 (0.70), 7.847 (0.69), 8.339(1.66), 8.362 (1.57), 8.657 (3.43), 11.593(1.96). (72% of theory)

Example 55N-(2,6-Dichlorophenyl)-1-(2,4-difluorophenyl)-7-(dimethylamino)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide

100 mg (0.29 mmol) of the compound from example 36A were initiallycharged in 3 ml of DMF, 132 mg (0.35 mmol) of HATU and 119 mg (0.93mmol) of DIPEA were added, and the mixture was stirred at 20° C. for 30minutes. Then a mixture of 66 mg (0.4 mmol) of 2,6-dichloroaniline and29 mg (0.72 mmol) of NaH (60 percent in paraffin) was added and themixture was stirred at 23° C. for 18 hours. Subsequently, the mixturewas purified via preparative RP-HPLC (eluent: acetonitrile/watergradient with 0.1% formic acid). This gave 27 mg (19% of theory) of thetitle compound.

LC-MS (Method 1): R_(t)=1.38 min; m/z=523.3 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.009 (1.63), 0.007 (1.55), 2.689(15.32), 2.730 (12.82), 2.889 (16.00), 2.965 (4.17), 6.953 (6.16), 6.976(6.30), 7.328 (2.09), 7.352 (3.89), 7.372 (5.08), 7.392 (4.16), 7.563(1.58), 7.575 (15.18), 7.586 (2.51), 7.595 (12.02), 7.605 (1.69), 7.837(1.53), 7.844 (2.57), 7.859 (2.51), 7.951 (1.95), 8.332 (6.93), 8.355(6.69), 8.685 (13.85), 12.019 (7.76).

Example 56rac-N-[1-(2,6-Dichlorophenyl)-2,2,2-trifluoroethyl]-1-(2,4-difluorophenyl)-7-(dimethylamino)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide

200 mg (0.58 mmol) of the compound from example 36A und 283 mg (1.2mmol) of 1-(2,6-dichlorophenyl)-2,2,2-trifluoroethanamine were initiallycharged in 4 ml of DMF, 210 mg (1.6 mmol) of DIPEA and 422 mg (0.81mmol) of PyBOP were added, and the mixture was stirred at 23° C. for 40minutes. The reaction mixture was then adjusted to pH 1 with 1 M aqueoushydrochloric acid, and the precipitated solid was then filtered off withsuction and washed with water and petroleum ether. This gave 300 mg (86%of theory, containing 0.25 eq. of DMF) of the title compound.

LC-MS (Method 1): R_(t)=1.36 min; m/z=571.0 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.001 (16.00), 0.006 (0.72), 1.242(0.19), 1.258 (0.19), 1.713 (0.27), 1.722 (0.31), 1.730 (0.67), 1.737(0.27), 1.746 (0.25), 2.731 (2.00), 2.890 (2.47), 2.946 (0.87), 2.991(0.45), 3.001 (0.49), 3.007 (0.62), 3.017 (0.60), 3.024 (0.38), 3.034(0.25), 6.922 (0.96), 6.945 (0.97), 7.028 (0.15), 7.052 (0.20), 7.067(0.21), 7.310 (0.24), 7.329 (0.27), 7.423 (0.17), 7.443 (0.14), 7.489(0.45), 7.509 (1.14), 7.529 (0.87), 7.564 (0.36), 7.591 (0.82), 7.611(0.50), 7.645 (0.69), 7.665 (0.52), 7.735 (0.15), 7.754 (0.15), 7.815(0.15), 7.830 (0.15), 7.951 (0.33), 8.315 (1.18), 8.338 (1.08), 8.621(0.72), 11.803 (0.29), 11.822 (0.27).

In analogy to Example 56, the example compounds shown in Table 6 wereprepared by reacting the compound from Example 36A with the appropriateamines (or salts thereof) under the reaction conditions described.Differences are specified in the respective examples.

TABLE 6 Ex. Analytical data 57 1-(2,4-Difluorophenyl)-7-(dimethylamino)-4- LC-MS (Method 1): R_(t) = 1.29 min; m/z =oxo-N-[2-(trifluoromethyl)phenyl]-1,4-dihy- 469.3 [M + H]⁺.dro-1,8-naphthyridine-3-carboxamide ¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]:

-0.009 (0.87), -0.001 (16.00), 0.005 (0.30), 0.007 (0.48), 2.958 (0.27),6.938 (0.37), 6.961 (0.36), 7.322 (0.17), 7.343 (0.31), 7.361 (0.18),7.594 (0.12), 7.673 (0.10), 7.693 (0.17), 7.712 (0.10), 7.746 (0.20),7.765 (0.18), 7.824 (0.10), 7.830 (0.16), 7.845 (0.16), 8.311 (0.22),8.331 (0.21), 8.347 (0.44), 8.369 (0.41), 8.724 (0.83), 12.669 (0.40). 3d at 23° C.; purification by preparative HPLC (eluent:acetonitrile/water gradient with 0.1% formic acid). (27% of theory) 58N- [2-Chloro-6-(trifluoromethyl)benzyl]-1- LC-MS (Method 1): Rt = 1.23min; m/z = (2,4-difluorophenyl)-7-(dimethylamino)-4- 537.3 [M + H]⁺.oxo-1,4-dihydro-l,8-naphthyridine-3-carboxamide ¹H-NMR (400 MHz,DMSO-d₆) δ [ppm]:

1.244 (3.96), 1.259 (5.15), 1.275 (2.54), 2.889 (3.79), 2.928 (9.26),4.791 (6.78), 6.873 (6.91), 6.896 (7.09), 7.318 (2.92), 7.323 (3.02),7.572 (2.88), 7.619 (2.39), 7.639 (5.38), 7.659 (3.27), 7.790 (3.43),7.805 (3.57), 7.818 (6.03), 7.838 (4.78), 7.905 (5.21), 7.925 (4.46),8.188 (7.85), 8.211 (7.45), 8.588 (16.00), 10.251 (2.62), 10.264 (5.29),10.276 (2.47). (86% of theory) 591-(2,4-Difluorophenyl)-7-(dimethylamino)-4- LC-MS (Method 1): R_(t) =1.21 min; m/z = oxo-N- [2-(trifluoromethyl)benzyl]-1,4-dihy- 503.4 [M +H]⁺. dro-1,8-naphthyridine-3-carboxamide ¹H-NMR (400 MHz, DMSO-d₆) δ[ppm]:

-0.010 (2.01), 0.007 (1.99), 2.940 (7.80), 4.728 (5.35), 4.743 (5.41),6.899 (7.30), 6.922 (7.44), 7.317 (2.38), 7.322 (2.51), 7.484 (1.65),7.503 (3.70), 7.522 (2.30), 7.548 (1.63), 7.555 (1.70), 7.573 (2.43),7.577 (2.54), 7.580 (2.51), 7.588 (3.28), 7.596 (2.10), 7.607 (5.24),7.657 (2.95), 7.676 (3.89), 7.741 (4.52), 7.761 (4.24), 7.779 (1.88),7.786 (3.19), 7.801 (3.15), 7.808 (1.76), 8.263 (8.28), 8.286 (7.89),8.573 (16.00), 10.449 (2.12), 10.464 (4.38), 10.479 (2.00). (75% oftheory) 60 1-(2,4-Difluorophenyl)-7-(dimethylamino)- LC-MS (Method 1):R_(t) = 1.22 min; m/z = N-[2-fluoro-6-(trifluoromethyl)benzyl]-4- 521.3[M + H]⁺. oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide ¹H-NMR (400MHz, DMSO-d₆) δ [ppm]:

0.007 (3.36), 2.366 (2.57), 2.709 (2.59), 2.730 (0.61), 2.929 (6.92),4.744 (3.85), 6.878 (6.28), 6.901 (6.36), 7.298 (1.15), 7.320 (2.22),7.341 (1.24), 7.543 (1.40), 7.550 (1.41), 7.573 (2.16), 7.592 (1.56),7.599 (1.38), 7.628 (2.72), 7.641 (5.46), 7.657 (16.00), 7.758 (1.32),7.773 (1.58), 7.779 (2.63), 7.794 (2.62), 7.801 (1.49), 7.816 (1.25),8.209 (6.65), 8.232 (6.36), 8.571 (11.91), 10.338 (1.95), 10.351 (3.90),10.364 (1.83). (81% of theory)

Example 611-(2,4-Difluorophenyl)-7-[(3S)-3-fluoropyrrolidin-1-yl]-4-oxo-N-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

100 mg (0.26 mmol) of the compound from example 45A were initiallycharged in 2.9 ml of DMF, 117 mg (0.31 mmol) of HATU and 106 mg (0.82mmol) of DIPEA were added, and the mixture was stirred at 20° C. for 30minutes. Then 54 mg (0.36 mmol) of 1-adamantanamine were added and themixture was then stirred at 20° C. for 2 hours. Subsequently, themixture was purified via preparative HPLC (eluent: acetonitrile/watergradient with 0.1% formic acid). This gave 103 mg (77% of theory) of thetitle compound.

LC-MS (Method 1): R_(t)=1.38 min; m/z=523.3 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.008 (1.49), 0.008 (1.35), 1.157(2.39), 1.175 (4.83), 1.193 (2.46), 1.356 (0.71), 1.674 (7.25), 1.988(8.83), 2.058 (16.00), 4.003 (0.70), 4.021 (2.07), 4.038 (2.06), 4.056(0.68), 6.763 (0.54), 6.785 (0.56), 7.323 (0.65), 7.782 (0.40), 7.790(0.66), 7.805 (0.66), 8.138 (1.19), 8.292 (1.32), 8.314 (1.29), 8.491(4.34), 9.938 (2.58).

In analogy to Example 61, the example compounds shown in Table 7 wereprepared by reacting the compound from Example 45A with the appropriateamines (or salts thereof) under the reaction conditions described.Differences are specified in the respective examples.

TABLE 7 Ex. Analytical data 62 1-(2,4-Difluorophenyl)-7-[(3S,)-3-fluoro-LC-MS (Method 1): R_(t) = 1.24 min pyrrolidin-1-yl]-N-(3-fluorotricy- MS(ESpos): m/z = 541.3 [M + H]⁺clo[3.3.1.1^(3,7)]dec-1-yl)-4-oxo-1,4-dihydro- ¹H-NMR (400 MHz, CDCl₃) δ[ppm]: 0.000 1,8-naphthyridine-3-carboxamide (1.22), 0.016 (1.21), 0.077(0.68), 1.231 (0.26),

1.296 (1.42), 1.309 (1.45), 1.441 (0.77), 1.592 (16.00), 1.733(0.25),1.754(0.25), 1.889(1.68), 1.950 (1.39), 2.053 (1.22), 2.083 (2.24),2.138 (1.82), 2.169 (0.98), 2.324 (0.52), 2.378 (3.30), 2.449 (0.56),2.794 (0.45), 2.812 (0.99), 2.892 (3.80), 2.965 (4.40), 3.488 (0.35),3.601 (0.79), 5.242 (0.24), 5.370 (0.24), 6.540 (0.62), 6.561 (0.61),7.006 (0.79), 7.026 (1.24), 7.046 (1.69), 7.065 (0.86), 7.348 (0.51),7.368 (0.89), 7.383 (0.88), 7.404 (0.39), 7.528 (0.44), 8.025 (0.47),8.442 (3.20), 8.464 (3.08), 8.639 (5.60), 10.109 (1.88). (87% of theory)63 1-(2,4-Difluorophenyl)-N-(4-fluorobicy-clo[2.2.2]oct-1-yl)-7-[(3S)-3-fluoropyrroli-din-1-yl]-4-oxo-1,4-dihydro-1,8-naphthy- ridine-3-carboxamide

LC-MS (Method 1): R_(t) = 1.18 min MS (ESpos): m/z = 515.3 [M + H]⁺¹H-NMR (400 MHz, CDCl₃) δ [ppm]: -0.140 (0.04), 0.001 (0.37), 0.017(0.29), 0.078 (0.19), 0.155 (0.04), 1.421 (0.08), 1.441 (0.12), 1.576(16.00), 1.937 (0.28), 1.951 (0.53), 1.967 (0.53), 1.977 (0.58), 1.992(0.37), 2.132 (0.03), 2.236 (0.64), 2.258 (0.61), 2.276 (0.48), 2.373(0.04), 2.449 (0.13), 2.794 (0.12), 2.812 (0.13), 2.893 (0.28), 2.965(0.35), 3.177 (0.03), 3.594 (0.10), 5.243 (0.03), 5.377 (0.03), 6.536(0.08), 6.556 (0.08), 7.006 (0.17), 7.027 (0.16), 7.046 (0.23), 7.065(0.11), 7.340 (0.07), 7.361 (0.12), 7.375 (0.12), 7.395 (0.06), 7.529(0.12), 8.027 (0.04), 8.429 (0.48), 8.451 (0.47), 8.620 (0.81), 9.983(100% of theory) (0.29). 64 1-(2,4-Difluorophenyl)-7-[(3S)-3-fluoro-LC-MS (Method 2): R_(t) = 2.82 minpyrrolidin-1-yl]-4-oxo-N-[(2S)-1,1,1-tri- MS (ESpos): m/z = 499.0 [M +H]⁺ fluorobutan-2-yl]-1,4-dihydro-1,8-naphthy- ¹H-NMR (400 MHz, DMSO-d₆)δ [ppm]: ridine-3-carboxamide -0.150 (0.56), -0.048 (0.52), -0.042(0.74), -0.038

(0.83), -0.035 (0.90), -0.033 (0.93), -0.031 (1.01), -0.028 (1.10),-0.026 (1.26), -0.023 (1.40), -0.021 (1.53), -0.018 (1.77), -0.016(2.10), -0.014 (2.33), -0.012 (3.16), -0.009 (6.86), -0.007 (6.14),-0.006 (7.26), 0.004 (4.31), 0.006 (3.08), 0.007 (4.66), 0.010 (1.10),0.013 (0.63), 0.015 (0.47), 0.018 (0.40), 0.145 (0.56), 0.950 (7.53),0.968 (16.00), 0.987 (7.73), 1.146 (0.34), 1.156 (0.33), 1.169 (0.46),1.174 (0.59), 1.581 (0.39), 1.599 (1.18), 1.617 (1.60), 1.624 (1.41),1.634 (1.83), 1.643 (1.66), 1.652 (1.56), 1.660 (1.77), 1.678 (1.30),1.697 (0.38), 1.833 (0.51), 1.852 (1.38), 1.861 (1.57), 1.870 (1.57),1.880(1.73), 1.886(1.53), 1.896(1.36), 1.904 (1.17), 1.914 (1.01), 1.987(0.93), 2.166 Workup: Precipitate the product with 1M (0.83), 2.327(0.76), 2.332 (0.60), 2.366 (0.84), aqueous hydrochloric acid and waterand 2.519 (3.20), 2.521 (3.13), 2.523 (3.42), 2.526 then filter off theprecipitate. (3.67), 2.558 (0.99), 2.560 (0.80), 2.563 (0.66), (86% oftheory) 2.565 (0.58), 2.568 (0.53), 2.570 (0.50), 2.573 (0.42), 2.575(0.33), 2.578 (0.33), 2.587 (0.33), 2.665 (0.55), 2.669 (0.69), 2.674(0.52), 2.709 (0.89), 3.132 (0.37), 3.496 (0.81), 3.690 (0.92), 4.735(1.51), 4.747 (1.40), 4.771 (0.78), 5.278 (0.44), 5.402 (0.55), 5.510(0.34), 5.753 (4.85), 6.807 (1.77), 7.324 (2.28), 7.546 (0.78), 7.569(1.54), 7.587 (1.29), 7.812 (1.76), 7.831 (1.67), 8.136 (0.79), 8.316(4.26), 8.338 (4.02), 8.631 (10.61), 10.479(4.79), 10.503(4.55). 651-(2,4-Difluorophenyl)-7-[(3S)-3-fluoro- LC-MS (Method 1): R_(t) = 1.29min pyrrolidin-1-yl]-4-oxo-N-[1,1,1-trifluoro-4- MS (ESpos): m/z = 527.3[M + H]⁺ methylpentan-2-yl]-1,4-dihydro-1,8-naphthy- ¹H-NMR (400 MHz,CDCl₆) δ [ppm]: 0.001 ridine-3-carboxamide (diastereomer mixture)(0.58), 0.017 (0.41), 0.078 (0.30), 0.959 (1.73),

0.975 (1.96), 0.984 (3.35), 1.001 (3.17), 1.232 (0.09), 1.379 (0.07),1.396 (0.06), 1.442 (0.38), 1.459 (0.11), 1.492 (0.12), 1.508 (0.13),1.518 (0.12), 1.576 (16.00), 1.602(0.52), 1.611 (0.65), 1.619 (0.37),1.636 (0.42), 1.645 (0.30), 1.714 (0.32), 1.724 (0.41), 1.742 (0.32),1.752 (0.52), 1.758 (0.35), 1.768 (0.16), 1.778 (0.40), 1.786 (0.49),1.795 (0.26), 1.802 (0.22), 1.811 (0.26), 1.821 (0.16), 1.826 (0.16),1.837 (0.09), 2.069 (0.08), 2.153 (0.08), 2.280 (0.06), 2.384 (0.11),2.450 (0.21), 2.634 (0.36), 2.795 (0.16), 2.813 (0.23), 2.893 (0.24),2.966 (0.30), 3.612 (0.30), 4.877 (0.15), 4.895 (0.24), 4.920 (0.24),4.929 (0.16), 4.939 (0.13), 4.947 (0.10), 5.245 (0.08), 5.379 (0.09),6.560 (0.22), 7.006 (0.26), 7.040 (92% of theory) (0.52), 7.060 (0.68),7.078 (0.35), 7.280 (0.28), 7.364 (0.21), 7.385 (0.36), 7.399 (0.36),7.421 (0.17), 7.529 (0.22), 8.450 (1.52), 8.472 (1.49), 8.697 (1.99),10.362 (0.46), 10.386 (0.46). 661-(2,4-Difluorophenyl)-7-[(3S)-3-fluoro- LC-MS (Method 2): R_(t) = 2.95min pyrrolidin-1-yl]-4-oxo-N-[1,1,1-trifluoropen- MS (ESpos): m/z =513.1 [M + H]⁺ tan-2-yl]-1,4-dihydro-1,8-naphthyridine-3- ¹H-NMR (400MHz, DMSO-d₆) δ [ppm]: carboxamide -0.151 (0.40), -0.009 (3.50), 0.007(3.30), 0.144 (diastereomer mixture) (0.41), 0.866 (0.27), 0.894 (7.06),0.912 (16.00),

0.930 (8.28), 0.998 (0.63), 1.067 (0.57), 1.146 (0.48), 1.168 (0.59),1.231 (0.25), 1.280 (0.26), 1.299 (0.59), 1.317 (0.99), 1.335 (1.38),1.355 (2.83), 1.373 (1.58), 1.391 (1.13), 1.410(0.91), 1.433 (1.07),1.444 (1.40), 1.464 (1.26), 1.480 (0.73), 1.497 (0.45), 1.594 (0.59),1.606 (0.60), 1.621 (0.88), 1.629 (1.55), 1.641 (1.14), 1.655 (1.61),1.667 (1.09), 1.678 (0.85), 1.690 (0.65), 1.739 (0.85), 1.748 (1.00),1.765 (1.39), 1.772 (1.51), 1.781 (1.19), 1.790(1.30), 1.796 (0.94),1.815 (0.53), 1.823 (0.45), 2.182 (0.85), 2.225 (0.67), 2.322 (0.46),2.326 (0.53), 2.331 (0.40), 2.365 (0.64), 2.522 (1.03), 2.664 (0.37),2.669 (0.45), 2.689 (0.62), 2.709 (0.66), 2.730 (0.62), 2.889 (0.78),3.090 (0.45), 3.136 (0.33), 3.486 Workup: Precipitate the product with1M (0.70), 3.697 (0.77), 4.773 (0.73), 4.797 (1.25), aqueoushydrochloric acid and water and 4.816 (1.27), 4.835 (0.70), 5.283(0.36), 5.409 then filter off the precipitate. (0.46), 5.512 (0.26),6.804 (1.49), 6.821 (1.46), (90% of theory ) 7.302 (1.11), 7.324 (2.12),7.342 (1.19), 7.546 (0.65), 7.566 (1.37), 7.588 (1.15), 7.792 (0.91),7.813 (1.86), 7.829 (1.85), 7.850 (0.81), 8.311 (3.82), 8.334 (3.68),8.629 (9.55), 10.474 (4.44), 10.498 (4.28). 671-(2,4-Difluorophenyl)-7-[(3S)-3-fluoro-pyrrolidin-1-yl]-4-oxo-N-(2,2,2-trifluoro-ethyl)-1,4-dihydro-1,8-naphthyridine-3-car- boxamide

LC-MS (Method 1): R_(t) = 1.07 min MS (ESpos): m/z = 471.2 [M + H]⁺¹H-NMR (400 MHz, CDCl₃) δ [ppm]: 0.001 (0.23), 0.017 (0.25), 0.079(0.15), 1.442 (0.09), 1.571 (16.00), 2.156 (0.04), 2.390 (0.06), 2.450(0.09), 2.794 (0.06), 2.894 (0.08), 2.966 (0.09), 3.608 (0.16), 4.098(0.11), 4.118 (0.14), 4.137 (0.17), 4.158 (0.14), 4.177 (0.10), 5.243(0.05), 5.375 (0.05), 6.575 (0.12), 7.006 (0.11), 7.047 (0.27), 7.066(0.35), 7.086 (0.18), 7.365 (0.11), 7.386 (0.19), 7.400 (0.19), 7.421(0.08), 7.529 (0.11), 8.460 (0.82), 8.470 (0.06), 8.482 (0.80), 8.492(0.04), 8.694 (1.41), 8.705 (0.06), 10.563 (0.14), 10.579 (0.25), 10.594(0.13). Workup: Precipitate the product with 1M aqueous hydrochloricacid and water and then filter off the precipitate. (91% of theory) 681-(2,4-Difluorophenyl)-7-[(3S)-3-fluoro- LC-MS (Method 1): R_(t) = 1.12min pyrrolidin-1-yl]-4-oxo-N-[1-(trifluor- MS (ESpos): m/z = 497.3 [M +H]⁺ methyl)cyclopropyl]-1,4-dihydro-1,8-naph- ¹H-NMR (400 MHz, CDCl₃) δ[ppm]: 0.016 thyridine-3-carboxamide (0.30), 0.078 (0.15), 1.234 (0.52),1.354 (0.11),

1.371 (0.17), 1.391 (1.08), 1.416 (0.12), 1.431 (0.07), 1.441 (0.18),1.502 (0.05), 1.580 (16.00), 2.059 (0.06), 2.150 (0.06), 2.380 (0.08),2.450 (0.14), 2.794 (0.10), 2.893 (0.23), 2.965 (0.27), 3.607 (0.23),5.237 (0.06), 5.368 (0.07), 6.554 (0.18), 6.570 (0.17), 7.006 (0.13),7.039 (0.36), 7.058 (0.48), 7.078 (0.24), 7.353 (0.15), 7.373 (0.26),7.388 (0.27), 7.409 (0.13), 7.529 (0.10), 8.438 (0.91), 8.460 (0.88),8.469 (0.07), 8.677 (1.57), 8.704 (0.07), 10.627 (0.63). (94% of theory)69 1-(2,4-Difluorophenyl)-7-[(3S)-3-fluoro- LC-MS (Method 1): R_(t) =1.23 min pyrrolidin-1-yl]-4-oxo-N-[1,1,1-trifluoro-3- MS (ESpos): m/z =513.3 [M + H]⁺ methylbutan-2-yl]-1,4-dihydro-1,8-naphthy- ¹H-NMR (400MHz, CDCl₃) δ [ppm]: 0.000 ridine-3-carboxamide (0.84), 0.017 (0.61),0.078 (0.50), 0.863 (0.16), (diastereomer mixture) 0.976 (0.27), 0.995(0.27), 1.063 (4.55), 1.081

(4.67), 1.138 (4.58), 1.155 (4.44), 1.232 (0.20), 1.267 (0.14), 1.284(0.14), 1.293 (0.13), 1.441 (0.48), 1.584 (16.00), 2.064 (0.15), 2.089(0.14), 2.268 (0.22), 2.285 (0.47), 2.295 (0.51), 2.302 (0.62), 2.313(0.65), 2.320 (0.51), 2.330 (0.50), 2.347 (0.28), 2.384 (0.18), 2.450(0.34), 2.793 (0.23), 2.812 (0.60), 2.893 (1.00), 2.965 (1.23), 3.609(0.52), 4.754 (0.11), 4.765 (0.33), 4.775 (0.36), 4.790 (0.46), 4.797(0.44), 4.811 (0.34), 4.822 (0.32), 5.242 (0.15), 5.372 (0.15), 6.560(0.39), 7.006 (0.33), 7.044 (0.86), 7.063 (1.17), 7.082 (0.60), 7.366(0.35), 7.386 (0.62), 7.401 (0.63), 7.422 (0.29), 7.529 (0.30), 8.027(0.13), 8.480 (2.49), 8.502 (2.40), 8.700 (3.93), 10.580 (0.77), 10.605(0.76). Workup: Precipitate the product with 1M aqueous hydrochloricacid and water and then filter off the precipitate. (98% of theory) 701-(2,4-Difluorophenyl)-7-[(3S)-3-fluoro- LC-MS (Method 1): R_(t) = 1.24min pyrrolidin-1-yl]-N-( 1,1,1,3,3,3-hexafluoro- MS (ESpos): m/z = 539.2[M + H]⁺ propan-2-yl)-4-oxo-1,4-dihydro-1,8-naphthy- ¹H-NMR (400 MHz,CDCl₃) δ [ppm]: -0.140 ridine-3-carboxamide (0.11), 0.001 (0.99), 0.017(0.82), 0.079 (0.21),

0.155 (0.11), 1.265 (0.11), 1.557 (16.00), 2.101 (0.10), 2.152 (0.11),2.430 (0.12), 2.449 (0.24), 2.794 (0.16), 3.376 (0.10), 3.496 (0.21),3.505 (0.21), 3.624 (0.35), 5.235 (0.09), 5.371 (0.09), 5.554 (0.15),5.572 (0.35), 5.579 (0.18), 5.589 (0.44), 5.597 (0.38), 5.607 (0.33),5.614 (0.46), 5.625 (0.16), 5.632 (0.32), 5.650 (0.13), 6.586 (0.25),7.006 (0.21), 7.059 (0.55), 7.079 (0.75), 7.098 (0.37), 7.371 (0.24),7.391 (0.40), 7.407 (0.40), 7.426 (0.17), 7.529 (0.20), 8.469 (1.94),8.492 (1.89), 8.691 (2.87), 11.305 (0.64), 11.330 (0.63). Workup:Precipitate the product with 1M aqueous hydrochloric acid and water andthen filter off the precipitate. (11% of theory) 711-(2,4-Difluorophenyl)-7-[(3S)-3-fluoro- LC-MS (Method 1): R_(t) = 1.18min pyrrolidin-1-yl]-4-oxo-N- [1,1,1-trifluorobu- MS (ESpos): m/z =499.3 [M + H]⁺ tan-2-yl]-1,4-dihydro-1,8-naphthyridine-3- ¹H-NMR (400MHz, CDCl₃) δ [ppm]: 0.000 carboxamide (0.22), 0.016 (0.19), 0.078(0.13), 1.057 (0.57), (diastereomer mixture) 1.076 (1.25), 1.094 (0.62),1.231 (0.04), 1.440

(0.17), 1.457 (0.05), 1.485 (0.06), 1.501 (0.06), 1.511 (0.06), 1.590(16.00), 1.687 (0.05), 1.705 (0.10), 1.712 (0.05), 1.723 (0.12), 1.731(0.11), 1.740 (0.15), 1.749 (0.13), 1.759 (0.13), 1.766 (0.15), 1.778(0.05), 1.784 (0.12), 1.803 (0.04), 1.913 (0.04), 1.932 (0.11), 1.942(0.12), 1.950 (0.12), 1.961 (0.13), 1.967 (0.11), 1.977 (0.11), 1.986(0.09), 1.996 (0.09), 2.005 (0.05), 2.014 (0.04), 2.072 (0.03), 2.126(0.03), 2.399 (0.05), 2.451 (0.08), 2.795 (0.06), 2.812 (0.09), 2.893(0.08), 2.965 (0.10), 3.611 (0.14), 4.726 (0.05), 4.735 (0.06), 4.750(0.10), 4.759 (0.10), 4.769 (0.10), 4.778 (0.10), 4.785 (0.07), 4.794(0.06), 4.804 (0.04), 5.237 (0.04), 5.379 (0.04), 6.565 (0.10), 7.006(0.10), 7.045 (0.22), 7.064 (0.29), Workup: Precipitate the product with1M 7.083 (0.15), 7.364 (0.09), 7.385 (0.15), 7.399 aqueous hydrochloricacid and water and (0.15), 7.420 (0.07), 7.529 (0.09), 8.456 (0.66),then filter off the precipitate. 8.478 (0.65), 8.694 (0.97), 10.419(0.20), 10.443 (86% of theory) (0.20).

Example 721-(2,4-Difluorophenyl)-7-[(3R)-3-fluoropyrrolidin-1-yl]-4-oxo-N-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

100 mg (0.26 mmol) of the compound from example 44A were initiallycharged in 2.9 ml of DMF, 117 mg (0.31 mmol) of HATU and 106 mg (0.82mmol) of DIPEA were added, and the mixture was stirred at 20° C. for 30minutes. Then 54 mg (0.36 mmol) of 1-adamantanamine were added and themixture was stirred at 20° C. for 2 hours. Subsequently, the mixture waspurified directly via preparative HPLC (eluent: acetonitrile/watergradient with 0.1% formic acid). This gave 103 mg (77% of theory) of thetitle compound.

LC-MS (Method 1): R_(t)=1.38 min; m/z=523.3 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.150 (0.23), −0.041 (0.10), −0.023(0.69), −0.018 (0.95), −0.009 (3.93), −0.007 (3.54), 0.006 (1.08), 0.007(1.84), 0.011 (0.32), 0.013 (0.18), 0.016 (0.13), 0.146 (0.25), 1.156(1.38), 1.174 (2.79), 1.192 (1.39), 1.234 (0.24), 1.355 (0.69), 1.672(7.42), 1.825 (0.14), 1.988 (4.88), 2.057 (16.00), 2.182 (0.33), 2.215(0.29), 2.322 (0.25), 2.327 (0.32), 2.332 (0.22), 2.366 (0.28), 2.519(1.27), 2.521 (1.30), 2.523 (1.58), 2.558 (0.24), 2.560 (0.20), 2.563(0.17), 2.565 (0.13), 2.568 (0.14), 2.570 (0.12), 2.573 (0.13), 2.575(0.11), 2.665 (0.25), 2.669 (0.30), 2.674 (0.22), 2.709 (0.30), 3.161(1.88), 3.174 (1.86), 3.467 (0.26), 3.675 (0.25), 4.002 (0.39), 4.020(1.11), 4.038 (1.09), 4.056 (0.43), 4.073 (0.52), 4.086 (0.49), 4.099(0.18), 5.323 (0.11), 5.412 (0.14), 6.764 (0.58), 6.785 (0.57), 7.300(0.36), 7.321 (0.67), 7.339 (0.38), 7.565 (0.42), 7.585 (0.38), 7.767(0.35), 7.789 (0.69), 7.804 (0.68), 7.826 (0.30), 8.149 (0.45), 8.291(1.37), 8.313 (1.30), 8.490 (4.58), 8.519 (0.13), 9.937 (2.54).

Example 731-(2,4-Difluorophenyl)-7-(3,3-difluoropyrrolidin-1-yl)-4-oxo-N-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

100 mg (0.26 mmol) of the compound from example 43A were initiallycharged in 2.8 ml of DMF, 112 mg (0.3 mmol) of HATU and 101 mg (0.79mmol) of DIPEA were added, and the mixture was stirred at 20° C. for 30minutes. Then 52 mg (0.34 mmol) of 1-adamantanamine were added and themixture was stirred at 20° C. for 2 hours. Subsequently, the mixture waspurified via preparative HPLC (eluent: acetonitrile/water gradient with0.1% formic acid). This gave 76 mg (57% of theory) of the titlecompound.

LC-MS (Method 1): R_(t)=1.41 min; m/z=541.3 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.009 (0.75), 0.007 (0.74), 1.232(0.33), 1.672 (7.44), 2.057 (16.00), 2.365 (0.15), 2.709 (0.15), 3.161(2.40), 3.174 (2.48), 3.546 (0.24), 4.060 (0.26), 4.073 (0.71), 4.086(0.69), 4.099 (0.24), 6.791 (0.59), 6.813 (0.61), 7.306 (0.40), 7.328(0.78), 7.349 (0.43), 7.557 (0.41), 7.563 (0.43), 7.586 (0.69), 7.605(0.43), 7.612 (0.41), 7.770 (0.49), 7.785 (0.57), 7.791 (0.97), 7.806(0.96), 7.813 (0.55), 7.828 (0.46), 8.336 (1.86), 8.358 (1.78), 8.519(4.96), 9.897 (2.61).

In analogy to Example 73, the example compounds shown in Table 8 wereprepared by reacting the compound from Example 43A with the appropriateamines (or salts thereof) under the reaction conditions described.Differences are specified in the respective examples.

TABLE 8 Ex. Analytical data 74rac-1-(2,4-Difluorophenyl)-7-(3,3-difluoro- LC-MS (Method 1): R_(t) =1.22 min pyrrolidin-1-yl)-4-oxo-N-[1,1,1-trifluorobu- MS (ESpos): m/z =517.2 [M + H]⁺ tan-2-yl]-1,4-dihydro-1,8-naphthyridine-3- ¹H-NMR (400MHz, CDCl₃) δ [ppm]: 0.079 carboxamide (1.42), 1.057 (7.39), 1.076(15.90), 1.095

(7.93), 1.232 (5.14), 1.572 (16.00), 1.705 (1.42), 1.723 (1.66), 1.740(1.97), 1.766 (1.94), 1.784 (1.50), 1.964 (1.56), 2.450 (2.28), 3.619(2.76), 4.753 (1.34), 6.541 (2.25), 6.563 (2.32), 7.006 (1.26), 7.045(2.37), 7.065 (3.90), 7.078 (3.60), 7.360 (1.50), 7.380 (2.31), 7.394(2.41), 7.529 (1.20), 8.505 (8.37), 8.528 (7.99), 8.712 (12.30), 10.344(2.52), 10.368 (2.49). (88% of theory) 751-(2,4-Difluorophenyl)-7-(3,3-difluoro-pyrrolidin-1-yl)-4-oxo-N-[(2S)-1,1,1-tri-fluorobutan-2-yl]-1,4-dihydro-1,8-naphthy- ridine-3-carboxamide

(90% of theory) LC-MS (Method 1): R_(t) = 1.22 min MS (ESpos): m/z =517.2 [M + H]⁺ ¹H-NMR (400 MHz, CDCl₃) δ [ppm]: 0.001 (3.23), 0.017(2.20), 0.079 (1.12), 1.057 (7.43), 1.075 (16.00), 1.094 (7.94), 1.253(5.33), 1.442 (1.10), 1.587 (6.32), 1.705 (1.64), 1.723 (1.85), 1.730(1.63), 1.740 (2.10), 1.748 (1.79), 1.758 (1.81), 1.765 (2.06), 1.784(1.62), 1.935 (1.36), 1.945 (1.43), 1.953 (1.47), 1.963 (1.58), 1.980(1.25), 2.450 (2.19), 2.471 (2.26), 3.000 (0.76), 3.622 (2.74), 4.761(1.35), 6.541 (2.20), 6.563 (2.21), 7.006 (1.01), 7.045 (2.38), 7.059(3.52), 7.065 (3.84), 7.077 (3.64), 7.084 (3.12), 7.359 (1.55), 7.380(2.28), 7.394 (2.36), 7.416 (1.18), 7.529 (0.88), 8.505 (8.69), 8.527(8.30), 8.712 (12.29), 10.344 (2.49), 10.368 (2.49). 76rac-1-(2,4-Difluorophenyl)-7-(3,3-difluoro- LC-MS (Method 1): R_(t) =1.28 min pyrrolidin-1-yl)-4-oxo-N- [1,1,1-trifluoropen- MS (ESpos): m/z= 531.2 [M + H]⁺ tan-2-yl]-1,4-dihydro-1,8-naphthyridine-3- ¹H-NMR (400MHz, CDCl₃) δ [ppm]: 0.001 carboxamide (3.68), 0.017 (2.94), 0.079(1.31), 0.957

(7.45), 0.975 (16.00), 0.994 (8.03), 1.161 (4.06), 1.233 (1.72), 1.442(2.18), 1.461 (1.88), 1.479 (2.03), 1.497 (1.61), 1.583 (14.64), 1.686(1.15), 1.721 (1.97), 1.733 (1.47), 1.747 (2.16), 1.759 (1.56), 1.770(1.26), 1.782 (1.01), 1.841 (1.54), 1.859 (1.34), 2.450 (2.21), 2.470(2.11), 3.618 (2.48), 4.859 (1-21), 6.539 (2.05), 6.562 (2.05), 7.006(1-29), 7.043 (2.11), 7.063 (3.49), 7.076 (3.17), 7.358 (1.38), 7.379(2.09), 7.393 (2.17), 7.415 (1.10), 7.529 (1.23), 8.502 (8.83), 8.524(8.43), 8.710 (11.39), 10.325 (2.44), 10.349 (2.44). (82% of theory)

Example 771-(2,4-Difluorophenyl)-4-oxo-7-(3,3,4,4-tetrafluoropyrrolidin-1-yl)-N-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

110 mg (0.21 mmol, 86% purity) of the compound from example 46A wereinitially charged in 2.4 ml of DMF, 97 mg (0.26 mmol) of HATU and 88 mg(0.68 mmol) of DIPEA were added, and the mixture was stirred at 20° C.for 30 minutes. Then 45 mg (0.3 mmol) of 1-adamantanamine were added andthe mixture was stirred at 20° C. for 2 hours. Subsequently, the mixturewas purified via preparative HPLC (eluent: acetonitrile/water gradientwith 0.1% formic acid). This gave 61 mg (50% of theory) of the titlecompound.

LC-MS (Method 1): R_(t)=1.41 min; m/z=577.3 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 0.000 (16.00), 1.235 (0.38), 1.674(4.18), 2.060 (8.85), 3.161 (0.98), 3.175 (1.04), 4.069 (0.63), 4.083(0.61), 6.877 (1.25), 6.899 (1.26), 7.337 (0.45), 7.570 (0.31), 7.589(0.43), 7.612 (0.30), 7.787 (0.29), 7.809 (0.54), 7.823 (0.54), 7.846(0.27), 8.433 (1.51), 8.455 (1.40), 8.562 (2.73), 9.835 (1.41).

Example 781-(2,4-Difluorophenyl)-7-(1,1-dioxido-1,3-thiazolidin-3-yl)-4-oxo-N-[1,1-trifluoro-4-methylpentan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

80 mg (0.15 mmol, 80% purity) of the compound from example 50A wereinitially charged in 1.7 ml of DMF, 70 mg (0.18 mmol) of HATU and 63 mg(0.49 mmol) of DIPEA were added, and the mixture was stirred at 20° C.for 30 minutes. Then 59 mg (0.39 mmol) of1,1,1-trifluoro-4-methylpentan-2-amine hydrochloride were added and themixture was stirred at 20° C. for 2 hours. Then 1 ml of 1 M aqueoushydrochloric acid and 2 ml of water were added, and the precipitatedsolid was filtered off, washed with 2 ml of water and 1 ml of petroleumether and dried under high vacuum. This gave 72 mg (84% of theory) ofthe title compound.

LC-MS (Method 1): R_(t)=1.15 min; m/z=559.3 [M+H]⁺.

¹H-NMR (400 MHz, CDCl₃) δ [ppm]: −0.140 (0.90), 0.001 (7.91), 0.017(7.32), 0.079 (2.03), 0.155 (0.80), 0.937 (0.81), 0.957 (6.31), 0.965(6.32), 0.973 (7.22), 0.982 (7.57), 0.988 (9.90), 1.004 (9.53), 1.233(1.77), 1.343 (3.73), 1.430 (0.86), 1.442 (2.01), 1.580 (16.00), 1.621(4.52), 1.647 (2.46), 1.708 (1.59), 1.718 (1.97), 1.737 (1.56), 1.746(2.37), 1.773 (1.76), 1.799 (1.17), 2.450 (1.53), 2.602 (0.92), 2.794(1.57), 2.894 (1.25), 2.965 (1.59), 2.999 (0.85), 3.179 (0.78), 3.379(3.94), 3.397 (8.19), 3.414 (4.27), 3.986 (4.62), 4.003 (8.47), 4.021(3.86), 4.390 (4.78), 4.893 (0.90), 4.918 (0.94), 6.685 (5.10), 6.708(5.24), 7.006 (1.92), 7.064 (1.40), 7.084 (3.11), 7.104 (2.61), 7.370(1.09), 7.385 (1.41), 7.391 (1.53), 7.405 (1.57), 7.427 (0.86), 7.529(1.90), 8.616 (5.68), 8.639 (5.59), 8.757 (5.70), 10.146 (1.87), 10.170(1.82).

Example 791-(2,4-Difluorophenyl)-7-[(2-hydroxyethyl)amino]-4-oxo-N-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

100 mg (0.28 mmol) of the compound from example 40A were initiallycharged in 3.1 ml of DMF, 126 mg (0.33 mmol) of HATU and 114 mg (0.89mmol) of DIPEA were added, and the mixture was stirred at 20° C. for 30minutes. Then 59 mg (0.39 mmol) of 1-adamantanamine were added and themixture was stirred at 20° C. for 2 hours. Subsequently, the mixture waspurified via preparative HPLC (eluent: acetonitrile/water gradient with0.1% formic acid). This gave 77 mg (56% of theory) of the titlecompound.

LC-MS (Method 1): R_(t)=1.20 min; m/z=495.3 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.013 (0.84), −0.005 (16.00), 0.003(1.54), 0.011 (1.70), 1.665 (1.85), 2.047 (3.60), 3.025 (0.21), 3.305(14.58), 3.320 (2.20), 4.595 (0.20), 6.661 (0.24), 6.684 (0.27), 7.302(0.21), 7.541 (0.19), 7.760 (0.23), 7.775 (0.25), 7.940 (0.14), 8.132(0.18), 8.425 (0.71), 9.985 (0.44).

In analogy to Example 79, the example compounds shown in Table 9 wereprepared by reacting the compound from Example 40A with the appropriateamines (or salts thereof) under the reaction conditions described.Differences are specified in the respective examples.

TABLE 9 Ex. Analytical data 801-(2,4-Difluorophenyl)-7-[(2-hydroxyethyl)amino]-4-oxo-N-[1,1,1-trifluoro-4-methylpentan-2-yl]-1,4-dihydro-1,8-naphthy-ridine-3-carboxamide  

  (52% of theory) LC-MS (Method 1): R_(t) = 1.08 min MS (ESpos): m/z =499.3 [M + H]⁺ ¹H-NMR (400 MHz, CDCl₃) δ [ppm]: 0.000 (0.62), 0.009(16.00), 0.017 (0.54), 0.078 (1.39), 0.953 (1.91), 0.969 (2.16), 0.975(2.17), 0.981 (3.89), 0.997 (3.76), 1.590 (8.07), 1.635 (1.25), 1.709(0.55), 1.719 (0.66), 1.737 (0.54), 1.747 (0.83), 1.753 (0.57), 1.779(0.61), 1.791 (0.40), 1.801 (0.44), 2.449 (0.72), 2.599 (0.31), 2.601(0.42), 2.604 (0.53), 2.633 (1.92), 2.635 (1.25), 2.637 (0.96), 2.639(0.83), 2.641 (0.61), 2.644 (0.43), 2.646 (0.29), 2.649 (0.34), 2.794(0.78), 3.321 (0.51), 3.334 (1.26), 3.345 (1.44), 3.359 (0.71), 3.650(0.95), 3.662 (1.38), 3.674 (0.74), 4.889 (0.31), 4.913 (0.32), 5.459(0.38), 5.474 (0.66), 5.488 (0.38), 6.535 (1.92), 6.557 (1.98), 7.006(0.49), 7.032 (0.37), 7.052 (1.16), 7.073 (1.04), 7.091 (0.32), 7.282(0.47), 7.285 (0.32), 7.364 (0.46), 7.379 (0.49), 7.386 (0.61), 7.400(0.59), 7.407 (0.41), 7.421 (0.34), 7.529 (0.50), 8.379 (1.44), 8.401(1.39), 8.671 (2.40), 10.330 (0.62), 10.353 (0.60). 811-(2,4-Difluorophenyl)-7-[(2-hydroxyethyl)amino]-4-oxo-N-[1,1,1-trifluoropentan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide  

  (66% of theory) LC-MS (Method 1): R_(t) = 1.03 min MS (ESpos): m/z =485.1 [M + H]⁺ ¹H-NMR (400 MHz, CDCl₃) δ [ppm]: 0.009 (16.00), 0.078(1.32), 0.953 (2.90), 0.972 (6.47), 0.990 (3.32), 1.268 (0.49), 1.456(0.71), 1.473 (0.75), 1.592 (5.81), 1.718 (0.94), 1.730 (0.71), 1.744(0.98), 1.756 (0.76), 1.768 (0.62), 1.828 (0.76), 2.053 (0.81), 2.450(0.67), 2.795 (0.70), 3.334 (2.18), 3.345 (2.48), 3.359 (1.19), 3.499(2.54), 3.650 (1.68), 3.662 (2.43), 4.853 (0.54), 5.478 (1.10), 6.535(3.40), 6.557 (3.46), 7.006 (0.52), 7.034 (0.80), 7.054 (2.29), 7.074(2.10), 7.092 (0.63), 7.362 (0.56), 7.383 (0.82), 7.397 (0.84), 7.529(0.52), 8.381 (2.56), 8.403 (2.49), 8.665 (5.40), 10.366 (1.05), 10.390(1.04).

Example 821-(2,4-Difluorophenyl)-7-[(2-hydroxyethyl)(methyl)amino]-4-oxo-N-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

100 mg (0.27 mmol) of the compound from example 39A were initiallycharged in 3 ml of DMF, 121 mg (0.32 mmol) of HATU and 110 mg (0.85mmol) of DIPEA were added, and the mixture was stirred at 20° C. for 30minutes. Then 56 mg (0.37 mmol) of 1-adamantanamine were added and themixture was stirred at 20° C. for 2 hours. Subsequently, the mixture waspurified via preparative HPLC (eluent: acetonitrile/water gradient with0.1% formic acid). This gave 92 mg (68% of theory) of the titlecompound.

LC-MS (Method 1): R_(t)=1.19 min; m/z=509.2 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.150 (0.24), −0.023 (0.16), −0.020(0.15), −0.009 (2.07), 0.007 (1.93), 0.145 (0.23), 1.146 (0.09), 1.168(0.83), 1.174 (0.20), 1.233 (0.21), 1.270 (0.15), 1.671 (7.32), 1.987(0.25), 2.055 (16.00), 2.322 (0.13), 2.327 (0.20), 2.365 (0.17), 2.523(0.40), 2.669 (0.21), 2.674 (0.16), 2.709 (0.18), 3.020 (0.25), 3.162(2.25), 3.173 (2.27), 4.073 (0.44), 4.087 (0.43), 4.648 (0.12), 6.578(0.11), 6.903 (0.34), 7.285 (0.37), 7.290 (0.40), 7.306 (0.74), 7.312(0.77), 7.328 (0.40), 7.332 (0.42), 7.526 (0.38), 7.533 (0.39), 7.556(0.66), 7.574 (0.40), 7.581 (0.38), 7.747 (0.44), 7.762 (0.54), 7.769(0.88), 7.784 (0.86), 7.790 (0.51), 7.805 (0.43), 8.143 (1.20), 8.231(0.74), 8.254 (0.73), 8.473 (5.19), 9.954 (2.53).

Example 831-(2,4-Difluorophenyl)-7-[(2-fluoroethyl)amino]-4-oxo-N-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

100 mg (0.17 mmol, 77% purity) of the compound from example 41A wereinitially charged in 2.4 ml of DMF, 96 mg (0.25 mmol) of HATU and 87 mg(0.68 mmol) of DIPEA were added, and the mixture was stirred at 20° C.for 30 minutes. Then 45 mg (0.3 mmol) of 1-adamantanamine were added andthe mixture was stirred at 20° C. for 2 hours. Subsequently, the mixturewas purified via preparative HPLC (eluent: acetonitrile/water gradientwith 0.1% formic acid). This gave 92 mg (87% of theory) of the titlecompound. In addition, 11 mg (11% of theory) of the title compound fromExample 84 were obtained (for analysis see Example 84).

LC-MS (Method 1): R_(t)=1.25 min; m/z=497.1 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.009 (1.89), 0.007 (1.26), 1.174(0.32), 1.669 (7.54), 1.988 (0.63), 2.053 (16.00), 4.243 (0.76), 4.362(0.77), 5.753 (3.13), 6.692 (1.39), 6.714 (1.40), 7.293 (0.46), 7.316(0.83), 7.336 (0.45), 7.535 (0.54), 7.542 (0.55), 7.564 (0.77), 7.583(0.54), 7.590 (0.53), 7.763 (0.52), 7.778 (0.73), 7.785 (1.00), 7.800(1.00), 7.822 (0.48), 8.126 (0.44), 8.173 (1.35), 8.195 (1.26), 8.262(0.52), 8.459 (4.10), 9.957 (2.41).

Example 847-(Aziridin-1-yl)-1-(2,4-difluorophenyl)-4-oxo-N-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

As described in the preparation of the compound from Example 83, 100 mg(0.17 mmol) of the compound from Example 41A were used to obtain 11 mg(11% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.34 min; m/z=479.2 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.150 (1.66), −0.061 (0.29), −0.009(16.00), 0.007 (12.85), 0.146 (1.63), 1.147 (0.73), 1.670 (4.93), 2.055(10.44), 2.322 (1.15), 2.327 (1.55), 2.331 (1.20), 2.365 (1.43), 2.664(1.49), 2.669 (1.88), 2.709 (1.75), 2.934 (1.81), 3.285 (1.03), 3.460(0.27), 5.753 (5.19), 6.890 (1.66), 6.912 (1.65), 7.302 (0.31), 7.322(0.58), 7.342 (0.34), 7.552 (0.36), 7.571 (0.50), 7.600 (0.38), 7.761(0.39), 7.783 (0.61), 7.799 (0.61), 7.820 (0.29), 8.251 (1.83), 8.274(1.69), 8.474 (3.26), 9.944 (1.67).

In analogy to Example 83, the example compounds shown in Table 10 wereprepared by reacting the compound from Example 41A with the appropriateamines (or salts thereof) under the reaction conditions described.Differences are specified in the respective examples.

TABLE 10 Ex. Analytical data 85rac-1-(2,4-Difluorophenyl)-7-[(2-fluoroethyl)amino]-4-oxo-N-[1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-car-boxamide  

  (62% of theory) LC-MS (Method 1): R_(t) = 1.09 min MS (ESpos): m/z =473.2 [M + H]⁺ ¹H-NMR (400 MHz, CDCl3) δ [ppm]: 0.001 (0.93), 0.017(0.79), 1.054 (1.69), 1.073 (3.70), 1.091 (1.86), 1.570 (16.00), 1.722(0.35), 1.729 (0.30), 1.739 (0.43), 1.748 (0.36), 1.758 (0.35), 1.765(0.42), 1.783 (0.35), 1.933 (0.29), 1.943 (0.31), 1.951 (0.33), 1.961(0.35), 1.969 (0.30), 1.978 (0.28), 3.422 (0.41), 3.434 (0.57), 3.447(0.46), 3.488 (0.39), 3.501 (0.48), 3.514 (0.36), 4.338 (0.59), 4.455(0.57), 4.749 (0.32), 4.758 (0.32), 4.768 (0.29), 4.777 (0.30), 5.308(0.55), 5.325 (0.36), 5.339 (0.64), 5.353 (0.34), 6.551 (2.21), 6.573(2.25), 7.022 (0.32), 7.029 (0.45), 7.050 (1.36), 7.070 (1.29), 7.091(0.34), 7.363 (0.34), 7.378 (0.45), 7.385 (0.53), 7.399 (0.54), 7.405(0.33), 8.408 (1.71), 8.430 (1.64), 8.690 (2.98), 10.367 (0.57), 10.391(0.56). 86 rac-1-(2,4-Difluorophenyl)-7-[(2-fluoroethyl)amino]-4-oxo-N-[(2R)-1,1,1-trifluoropentan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide  

  (80% of theory) LC-MS (Method 1): R_(t) = 1.18 min MS (ESpos): m/z =487.2 [M + H]⁺ ¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 0.890 (4.26), 0.908(9.54), 0.926 (4.93), 1.156 (4.22), 1.174 (8.57), 1.191 (4.34), 1.293(0.33), 1.311 (0.65), 1.329 (0.91), 1.348 (1.13), 1.366 (1.05), 1.385(0.71), 1.403 (0.59), 1.437 (0.98), 1.457 (0.87), 1.589 (0.40), 1.601(0.41), 1.624 (1.05), 1.636 (0.79), 1.650 (1.11), 1.662 (0.77), 1.673(0.58), 1.685 (0.45), 1.735 (0.57), 1.744 (0.68), 1.768 (1.06), 1.777(0.82), 1.786 (0.91), 1.987 (16.00), 3.238 (1.12), 4.001 (1.31), 4.019(3.90), 4.037 (3.86), 4.055 (1.27), 4.248 (1.63), 4.365 (1.62), 4.787(0.88), 4.809 (0.90), 6.727 (2.72), 6.750 (2.78), 7.296 (0.91), 7.318(1.80), 7.339 (0.95), 7.537 (1.01), 7.544 (1.05), 7.563 (1.65), 7.586(1.05), 7.592 (1.00), 7.788 (0.71), 7.809 (1.46), 7.825 (1.47), 7.846(0.65), 8.195 (3.34), 8.217 (3.32), 8.601 (4.68), 10.499 (2.74), 10.523(2.63). 87 1-(2,4-Difluorophenyl)-7-[(2-fluoroethyl)amino]-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide  

  (88% of theory) LC-MS (Method 1): R_(t) = 1.10 min MS (ESpos): m/z =473.1 [M + H]⁺ ¹H-NMR (400 MHz, CDCl3) δ [ppm]: 0.001 (0.70), 0.017(0.67), 1.054 (2.82), 1.073 (6.18), 1.091 (3.08), 1.269 (0.84), 1.571(16.00), 1.704 (0.44), 1.722 (0.57), 1.730 (0.49), 1.739 (0.70), 1.748(0.60), 1.758 (0.60), 1.765 (0.71), 1.783 (0.56), 1.933 (0.48), 1.943(0.53), 1.952 (0.56), 1.962 (0.60), 1.969 (0.51), 1.979 (0.47), 2.054(1.54), 3.422 (0.69), 3.435 (0.96), 3.448 (0.77), 3.488 (0.65), 3.502(0.81), 3.515 (0.60), 4.338 (0.98), 4.456 (0.97), 4.749 (0.52), 4.758(0.53), 4.767 (0.50), 4.777 (0.51), 5.322 (0.60), 5.336 (1.10), 5.350(0.59), 6.551 (3.52), 6.573 (3.59), 7.022 (0.52), 7.029 (0.73), 7.050(2.28), 7.070 (2.18), 7.091 (0.57), 7.363 (0.60), 7.378 (0.75), 7.385(0.95), 7.399 (0.92), 7.405 (0.56), 7.420 (0.47), 8.408 (2.76), 8.430(2.69), 8.690 (4.93), 10.368 (0.96), 10.393 (0.94). 881-(2,4-Difluorophenyl)-7-[(2-fluoroethyl)amino]-4-oxo-N-[1,1,1-trifluoro-4-dihydro-1,8-naphthyridine-3-carboxamide  

  (81% of theory) LC-MS (Method 1): R_(t) = 1.21 min MS (ESpos): m/z =501.1 [M + H]⁺ ¹H-NMR (400 MHz, CDCl3) δ [ppm]: 0.002 (1.23), 0.018(0.96), 0.954 (3.69), 0.961 (3.35), 0.970 (4.10), 0.977 (3.90), 0.983(6.77), 1.000 (6.52), 1.251 (1.45), 1.269 (2.97), 1.287 (1.48), 1.562(16.00), 1.605 (0.50), 1.613 (0.98), 1.621 (0.57), 1.638 (0.74), 1.711(0.73), 1.721 (0.95), 1.739 (0.76), 1.749 (1.28), 1.755 (0.82), 1.784(0.91), 1.793 (0.54), 1.803 (0.60), 2.054 (5.63), 3.422 (0.69), 3.434(0.94), 3.447 (0.77), 3.487 (0.65), 3.501 (0.78), 3.514 (0.58), 4.123(1.22), 4.140 (1.19), 4.338 (0.99), 4.455 (0.98), 4.892 (0.54), 4.897(0.51), 4.916 (0.55), 5.308 (0.65), 5.322 (1.19), 5.336 (0.63), 6.548(3.79), 6.570 (3.87), 7.024 (0.60), 7.045 (1.87), 7.066 (1.71), 7.089(0.51), 7.364 (0.78), 7.378 (0.90), 7.385 (1.10), 7.399 (1.12), 7.406(0.70), 7.420 (0.61), 8.402 (2.82), 8.424 (2.74), 8.693 (4.00), 10.314(1.02), 10.338 (1.01). 891-(2,4-Difluorophenyl)-7-[(2-fluoroethyl)amino]-N-(1,1,1,3,3,3-hexafluoropropan-2-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide  

  Workup: Precipitate the product from water/1M aqueous hydrochloricacid and filter off the precipitate. (49% of theory) LC-MS (Method 1):R_(t) = 1.16 min MS (ESpos): m/z = 513.0 [M + H]⁺ ¹H-NMR (400 MHz,DMSO-d₆) δ [ppm]: −0.009 (7.65), 0.007 (6.55), 2.520 (2.86), 2.523(3.34), 2.525 (3.18), 3.244 (2.42), 4.249 (3.34), 4.367 (3.31), 6.293(1.94), 6.298 (1.86), 6.317 (2.05), 6.750 (5.02), 6.772 (5.07), 7.302(2.00), 7.306 (2.17), 7.309 (2.15), 7.322 (3.87), 7.328 (4.05), 7.344(2.18), 7.348 (2.17), 7.351 (2.07), 7.547 (2.40), 7.554 (2.64), 7.572(3.49), 7.576 (3.71), 7.595 (2.54), 7.602 (2.55), 7.799 (2.53), 7.814(3.05), 7.821 (4.81), 7.836 (5.18), 7.843 (2.65), 7.857 (2.68), 8.216(4.87), 8.239 (4.83), 8.278 (2.50), 8.290 (3.13), 8.705 (16.00), 11.489(5.43), 11.515 (5.18).

Example 901-(2,4-Difluorophenyl)-4-oxo-N-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)-7-[(2,2,2-trifluoroethyl)amino]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

73 mg (0.18 mmol) of the compound from example 47A were initiallycharged in 2 ml of DMF, 83 mg (0.22 mmol) of HATU and 76 mg (0.58 mmol)of DIPEA were added, and the mixture was stirred at 20° C. for 30minutes. Then 39 mg (0.26 mmol) of 1-adamantanamine were added and themixture was stirred at 20° C. for 2 hours. Subsequently, the mixture waspurified via preparative HPLC (eluent: acetonitrile/water gradient with0.1% formic acid). This gave 86 mg (88% of theory) of the titlecompound.

LC-MS (Method 1): R_(t)=1.35 min; m/z=533.3 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.150 (0.27), −0.009 (2.24), 0.007(2.13), 0.145 (0.26), 1.671 (7.23), 2.056 (16.00), 2.327 (0.23), 2.365(0.31), 2.669 (0.25), 2.709 (0.31), 3.842 (0.52), 6.782 (1.04), 6.804(1.05), 7.302 (0.41), 7.323 (0.76), 7.344 (0.42), 7.529 (0.49), 7.536(0.52), 7.554 (0.73), 7.577 (0.51), 7.584 (0.50), 7.754 (0.48), 7.769(0.58), 7.776 (0.96), 7.791 (0.95), 7.798 (0.54), 7.813 (0.47), 8.149(0.31), 8.271 (2.14), 8.293 (2.02), 8.387 (0.42), 8.511 (4.59), 9.896(2.62).

In analogy to Example 90, the example compounds shown in Table 11 wereprepared by reacting the compound from Example 47A or the compound fromExample 55A with the appropriate amines (or salts thereof) under thereaction conditions described. Differences are specified in therespective examples.

TABLE 11 Ex. Analytical data 911-(2,4-Difluorophenyl)-N-(3-fluorotricyclo[3.3.1.1^(3,7)]dec-1-yl)-4-oxo-7-[(2,2,2-trifluoroethyl)amino]-1,4-dihydro-1,8-naphthyridine-3-carboxamide  

  (62% of theory) LC-MS (Method 1): R_(t) = 1.21 min MS (ESpos): m/z =551.2 [M + H]⁺ ¹H-NMR (400 MHz, CDCl3) δ [ppm]: 0.009 (2.02), 0.078(0.26), 1.250 (0.62), 1.268 (1.29), 1.286 (0.65), 1.576 (16.00), 1.631(0.40), 1.891 (0.69), 1.940 (0.58), 2.053 (2.80), 2.083 (0.82), 2.132(0.59), 2.376 (1.07), 2.894 (0.75), 2.966 (0.89), 3.798 (0.25), 3.820(0.77), 3.837 (0.87), 3.842 (0.82), 3.859 (0.79), 3.881 (0.25), 4.104(0.18), 4.122 (0.52), 4.140 (0.53), 4.158 (0.17), 5.245 (0.48), 6.600(1.56), 6.622 (1.58), 7.006 (0.15), 7.024 (0.24), 7.031 (0.41), 7.044(0.67), 7.051 (0.65), 7.063 (0.74), 7.070 (0.59), 7.076 (0.40), 7.081(0.37), 7.351 (0.32), 7.365 (0.37), 7.372 (0.42), 7.385 (0.42), 7.394(0.30), 7.408 (0.24), 7.529 (0.15), 8.465 (1.55), 8.487 (1.50), 8.674(2.56), 9.991 (0.80). 921-(2,4-Difluorophenyl)-N-(3,5-difluorotricyclo[3.3.1.1^(3,7)]dec-1-yl)-4-oxo-7-[(2,2,2-trifluoroethyl)amino]-1,4-dihydro-1,8-naphthyridine-3-carboxamide  

  (33% of theory) LC-MS (Method 1): R_(t) = 1.13 min MS (ESpos): m/z =569.3 [M + H]⁺ ¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.150 (0.90), −0.009(7.71), 0.007 (7.47), 0.145 (0.97), 1.156 (2.58), 1.174 (5.20), 1.192(2.65), 1.804 (9.58), 1.902 (6.37), 1.987 (9.51), 2.072 (1.78), 2.112(1.99), 2.171 (3.19), 2.327 (3.45), 2.448 (1.58), 2.669 (1.05), 2.709(1.19), 3.161 (15.44), 3.174 (16.00), 3.842 (1.60), 4.020 (2.24), 4.038(2.24), 4.062 (1.58), 4.075 (4.33), 4.088 (4.28), 4.101 (1.51), 6.795(2.89), 6.818 (3.02), 7.305 (1.19), 7.326 (2.31), 7.347 (1.31), 7.532(1.36), 7.538 (1.51), 7.561 (2.24), 7.580 (1.53), 7.586 (1.51), 7.759(1.41), 7.774 (1.65), 7.781 (2.82), 7.796 (2.84), 7.817 (1.41), 8.279(6.13), 8.301 (5.84), 8.419 (1.26), 8.551 (13.67), 10.210 (6.91). 931-(2,4-Difluorophenyl)-4-oxo-7-[(2,2,2-trifluoroethyl)amino]-N-[1,1,1-trifluoropropan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide  

  (45% of theory) LC-MS (Method 1): R_(t) = 1.09 min MS (ESpos): m/z =495.1 [M + H]⁺ ¹H-NMR (400 MHz, CDCl₃) δ [ppm]: 0.001 (0.87), 0.016(0.49), 0.017 (0.80), 1.251 (0.34), 1.269 (0.71), 1.287 (0.37), 1.451(2.80), 1.468 (2.83), 1.566 (16.00), 2.054 (1.26), 2.630 (0.83), 2.634(0.30), 2.637 (0.20), 3.818 (0.41), 3.827 (0.36), 3.835 (0.40), 3.842(0.52), 3.849 (0.38), 3.857 (0.36), 3.866 (0.41), 4.122 (0.27), 4.140(0.27), 4.918 (0.24), 4.937 (0.24), 5.265 (0.36), 6.621 (1.63), 6.643(1.66), 7.042 (0.21), 7.049 (0.33), 7.065 (0.67), 7.068 (0.60), 7.084(0.69), 7.093 (0.41), 7.102 (0.30), 7.259 (0.24), 7.261 (0.42), 7.276(0.51), 7.280 (0.23), 7.382 (0.30), 7.401 (0.29), 8.479 (1.56), 8.501(1.52), 8.722 (1.17), 10.364 (0.37), 10.388 (0.36). 941-(2,4-Difluorophenyl)-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-7-[(2,2,2-trifluoroethyl)amino]-1,4-dihydro-1,8-naphthyridine-3-carboxamide  

  (45% of theory) LC-MS (Method 1): R_(t) = 1.10 min MS (ESpos): m/z =509.2 [M + H]⁺ ¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.009 (7.83), 0.007(6.82), 0.945 (7.20), 0.963 (16.00), 0.982 (7.83), 1.617 (1.49), 1.624(1.37), 1.634 (1.79), 1.643 (1.63), 1.652 (1.56), 1.659 (1.75), 1.678(1.35), 1.850 (1.25), 1.860 (1.49), 1.868 (1.53), 1.878 (1.70), 1.885(1.49), 1.895 (1.30), 1.903 (1.13), 2.523 (2.31), 3.851 (1.98), 3.869(1.96), 3.892 (1.42), 4.735 (1.44), 4.754 (1.37), 6.819 (3.40), 6.841(3.45), 7.306 (1.39), 7.328 (2.81), 7.345 (1.53), 7.534 (1.56), 7.542(1.63), 7.560 (2.64), 7.565 (2.69), 7.583 (1.68), 7.590 (1.63), 7.796(1.86), 7.805 (1.86), 7.819 (1.84), 8.300 (7.29), 8.322 (6.91), 8.467(1.63), 8.655 (6.11), 8.662 (5.52), 10.426 (4.88), 10.450 (4.72). 95rac-1-(2,4-Difluorophenyl)-4-oxo-7-[(2,2,2-trifluoroethyl)amino]-N-[1,1,1-trifluoro-4-methylpentan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide  

  (54% of theory) LC-MS (Method 1): R_(t) = 1.25 min MS (ESpos): m/z =537.1 [M + H]⁺ ¹H-NMR (400 MHz, CDCl₃) δ [ppm]: 0.002 (1.21), 0.018(0.98), 0.957 (3.49), 0.973 (3.84), 0.984 (6.39), 1.001 (6.32), 1.251(0.59), 1.269 (1.24), 1.287 (0.60), 1.559 (16.00), 1.609 (0.40), 1.617(0.79), 1.625 (0.46), 1.643 (0.60), 1.708 (0.56), 1.718 (0.76), 1.736(0.61), 1.746 (1.03), 1.752 (0.70), 1.775 (0.71), 1.797 (0.39), 2.054(2.17), 3.818 (0.79), 3.831 (0.85), 3.835 (0.89), 3.841 (0.82), 3.848(0.86), 3.853 (0.88), 3.857 (0.85), 3.870 (0.78), 4.123 (0.47), 4.141(0.46), 4.892 (0.42), 4.897 (0.39), 4.917 (0.43), 5.210 (0.48), 5.226(0.89), 5.242 (0.47), 6.619 (3.06), 6.641 (3.12), 7.044 (0.47), 7.063(1.28), 7.082 (1.15), 7.369 (0.62), 7.383 (0.69), 7.390 (0.77), 7.404(0.80), 7.411 (0.52), 7.426 (0.42), 8.478 (2.53), 8.500 (2.48), 8.735(3.20), 10.235 (0.79), 10.259 (0.78). 961-(2,4-Difluorophenyl)-4-oxo-7-[(2,2,2-trifluoroethyl)amino]-N-[1-(trifluoromethyl)cyclopentyl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide  

  (50% of theory) LC-MS (Method 1): R_(t) = 1.21 min MS (ESpos): m/z =535.1 [M + H]⁺ ¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.009 (2.42), 0.007(1.94), 1.174 (2.34), 1.731 (3.38), 1.749 (4.42), 1.773 (4.61), 1.790(3.12), 1.987 (4.41), 2.026 (2.74), 2.044 (3.04), 2.061 (3.19), 2.350(1.72), 2.365 (2.67), 2.384 (2.86), 2.418 (1.36), 3.823 (1.37), 3.847(1.84), 3.867 (1.87), 6.807 (3.27), 6.829 (3.31), 7.299 (1.38), 7.304(1.50), 7.321 (2.76), 7.326 (2.90), 7.342 (1.55), 7.347 (1.55), 7.532(1.76), 7.539 (1.85), 7.557 (2.72), 7.561 (2.71), 7.580 (1.80), 7.587(1.75), 7.762 (1.74), 7.777 (2.08), 7.784 (3.42), 7.799 (3.34), 7.805(1.86), 7.820 (1.63), 8.293 (6.84), 8.315 (6.47), 8.454 (1.57), 8.604(16.00), 10.523 (9.58). 971-(2,4-Difluorophenyl)-N-(4-fluorobicyclo[2.2.2]oct-1-yl)-4-oxo-7-[(2,2,2-trifluoroethyl)amino]-1,4-dihydro-1,8-naphthyridine-3-carboxamide  

  (59% of theory) LC-MS (Method 1): R_(t) = 1.16 min MS (ESpos): m/z =525.1 [M + H]⁺ ¹H-NMR (400 MHz, CDCl₃) δ [ppm]: 0.010 (3.66), 0.079(0.26), 1.233 (0.17), 1.251 (0.35), 1.269 (0.74), 1.287 (0.37), 1.566(16.00), 1.939 (0.49), 1.953 (0.93), 1.969 (0.95), 1.980 (1.01), 1.993(0.63), 2.054 (1.38), 2.234 (1.14), 2.246 (0.89), 2.255 (1.03), 2.274(0.83), 3.811 (0.21), 3.816 (0.49), 3.833 (0.54), 3.838 (0.50), 3.855(0.48), 4.123 (0.29), 4.140 (0.29), 5.205 (0.26), 6.594 (1.02), 6.616(1.03), 7.031 (0.24), 7.045 (0.44), 7.051 (0.41), 7.055 (0.26), 7.065(0.43), 7.070 (0.38), 7.076 (0.25), 7.082 (0.21), 7.344 (0.20), 7.358(0.22), 7.365 (0.25), 7.378 (0.26), 7.387 (0.19), 8.454 (0.99), 8.476(0.95), 8.657 (1.56), 9.864 (0.47). 981-(2,4-Difluorophenyl)-N-(4-methylbicyclo[2.2.2]oct-1-yl)-4-oxo-7-[(2,2,2-trifluoroethyl)amino]-1,4-dihydro-1,8-naphthyridine-3-carboxamide  

  (56% of theory) LC-MS (Method 1): R_(t) = 1.28 min MS (ESpos): m/z =521.2 [M + H]⁺ ¹H-NMR (400 MHz, CDCl₃) δ [ppm]: 0.001 (0.28), 0.017(0.22), 0.816 (1.69), 1.507 (0.44), 1.527 (0.51), 1.547 (0.58), 1.564(16.00), 2.021 (0.50), 2.041 (0.48), 2.061 (0.42), 3.816 (0.20), 3.832(0.22), 3.838 (0.20), 3.855 (0.20), 5.174 (0.10), 6.582 (0.44), 6.604(0.46), 7.006 (0.11), 7.023 (0.10), 7.037 (0.19), 7.044 (0.18), 7.056(0.19), 7.062 (0.16), 7.342 (0.09), 7.363 (0.11), 7.376 (0.12), 7.399(0.08), 7.529 (0.10), 8.464 (0.43), 8.486 (0.42), 8.674 (0.69), 9.766(0.19). 99rac-1-(2,4-Difluorophenyl)-7-[methyl(2,2,2-trifluoroethyl)amino]-4-oxo-N-[1,1,1-trifluoropropan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide  

  Compound from Example 55A and 1,1,1-trifluoropropan-2-amine LC-MS(Method 1): R_(t) = 1.18 min MS (ESpos): m/z = 509.2 [M + H]⁺ ¹H-NMR(400 MHz, DMSO-d₆) δ [ppm]: 1.168 (1.57), 1.232 (1.49), 1.269 (1.09),1.368 (15.88), 1.385 (16.00), 3.094 (6.92), 4.238 (0.99), 4.872 (1.17),4.892 (1.82), 4.911 (1.83), 4.930 (1.13), 7.099 (1.62), 7.120 (1.64),7.306 (1.51), 7.311 (1.61), 7.328 (2.88), 7.333 (3.00), 7.349 (1.64),7.354 (1.69), 7.547 (1.45), 7.570 (2.64), 7.595 (1.43), 7.777 (1.34),7.792 (1.49), 7.800 (1.54), 7.808 (1.57), 7.823 (1.38), 8.408 (4.61),8.431 (4.41), 8.692 (6.39), 8.700 (5.51), 10.428 (2.96), 10.451 (2.92).100 rac-1-(2,4-Difluorophenyl)-7-[methyl(2,2,2-trifluoroethyl)amino]-4-oxo-N-[1,1,1-trifluoropropan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide  

  (100% of theory) LC-MS (Method 1): R_(t) = 1.22 min MS (ESpos): m/z =523.2 [M + H]+ ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: −0.009 (6.06), 0.007(4.96), 0.950 (7.55), 0.968 (16.00), 0.987 (7.84), 1.168 (1.87), 1.233(1.40), 1.269 (1.13), 1.604 (1.17), 1.622 (1.56), 1.630 (1.41), 1.639(1.87), 1.648 (1.62), 1.657 (1.61), 1.665 (1.81), 1.683 (1.39), 1.854(1.34), 1.864 (1.54), 1.873 (1.55), 1.883 (1.71), 1.889 (1.50), 1.899(1.34), 1.908 (1.20), 1.918 (0.98), 2.327 (0.87), 2.365 (1.13), 2.523(1.71), 2.669 (0.82), 2.709 (1.03), 3.094 (5.27), 4.232 (0.96), 4.718(0.86), 4.742 (1.43), 4.762 (1.30), 7.102 (1.57), 7.123 (1.59), 7.312(1.54), 7.333 (2.90), 7.349 (1.59), 7.543 (1.60), 7.550 (1.63), 7.568(2.65), 7.592 (1.70), 7.598 (1.57), 7.803 (1.81), 7.813 (1.79), 7.827(1.76), 8.418 (4.92), 8.440 (4.73), 8.699 (6.82), 8.707 (6.06), 10.377(4.66), 10.401 (4.47).

Example 1011-(2,4-Difluorophenyl)-7-[(2-fluoroethyl)(methyl)amino]-4-oxo-N-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

100 mg (0.27 mmol) of the compound from example 42A were initiallycharged in 3 ml of DMF, 121 mg (0.32 mmol) of HATU and 110 mg (0.85mmol) of DIPEA were added, and the mixture was stirred at 20° C. for 30minutes. Then 56 mg (0.37 mmol) of 1-adamantanamine were added and themixture was stirred at 20° C. for 2 hours. Subsequently, the mixture waspurified via preparative HPLC (eluent: acetonitrile/water gradient with0.1% formic acid). This gave 46 mg (34% of theory) of the titlecompound.

LC-MS (Method 1): R_(t)=1.38 min; m/z=511.3 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.013 (1.34), 0.003 (1.24), 1.229(0.37), 1.667 (7.41), 1.983 (0.28), 2.052 (16.00), 2.322 (0.18), 2.664(0.20), 3.021 (0.65), 3.157 (1.10), 3.170 (1.12), 3.612 (0.28), 4.069(0.29), 4.082 (0.29), 4.328 (0.22), 4.438 (0.22), 5.749 (0.29), 6.938(0.82), 6.961 (0.82), 7.291 (0.38), 7.295 (0.41), 7.311 (0.76), 7.316(0.78), 7.331 (0.42), 7.337 (0.42), 7.536 (0.48), 7.543 (0.50), 7.562(0.74), 7.566 (0.74), 7.585 (0.49), 7.592 (0.47), 7.761 (0.47), 7.776(0.58), 7.783 (0.93), 7.798 (0.91), 7.804 (0.52), 7.819 (0.43), 8.279(1.06), 8.302 (1.01), 8.495 (4.56), 9.916 (2.39).

In analogy to Example 101, the example compounds shown in Table 12 wereprepared by reacting the compound from Example 42A with the appropriateamines (or salts thereof) under the reaction conditions described.Differences are specified in the respective examples.

TABLE 12 Ex. Analytical data 1021-(2,4-Difluorophenyl)-7-[(2-fluoroethyl)(methyl)amino]-N-(3-fluorotricyclo[3.3.1.1^(3,7)]dec-1-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide  

  (90% of theory) LC-MS (Method 1): R_(t) = 1.24 min MS (ESpos): m/z =529.3 [M + H]⁺ ¹H-NMR (400 MHz, CDCl3) δ [ppm]: 0.017 (0.33), 0.078(0.23), 1.043 (1.05), 1.059 (1.12), 1.232 (0.17), 1.581 (16.00), 1.632(0.29), 1.890 (0.44), 1.948 (0.36), 2.051 (0.26), 2.081 (0.54), 2.137(0.36), 2.380 (0.77), 2.450 (0.14), 2.794 (0.14), 2.893 (0.23), 2.965(0.30), 3.136 (1.37), 3.607 (0.16), 4.304 (0.19), 4.421 (0.19), 6.695(0.88), 6.718 (0.90), 7.006 (0.36), 7.027 (0.73), 7.047 (0.71), 7.066(0.19), 7.333 (0.20), 7.347 (0.23), 7.355 (0.27), 7.369 (0.27), 7.529(0.15), 8.453 (0.81), 8.476 (0.78), 8.636 (1.49), 10.081 (0.46). 1031-(2,4-Difluorophenyl)-7-[(2-fluoroethyl)(methyl)amino]-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide  

  (80% of theory) LC-MS (Method 2): R_(t) = 2.81 min MS (ESpos): m/z =487.0 [M + H]⁺ ¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.150 (1.09), −0.047(1.29), −0.039 (1.70), −0.036 (1.79), −0.034 (1.99), −0.031 (2.08),−0.029 (2.31), −0.027 (2.43), −0.024 (2.68), −0.022 (2.95), −0.019(3.40), −0.017 (3.89), −0.014 (4.70), −0.012 (5.89), −0.009 (12.50),−0.007 (10.42), 0.004 (3.50), 0.006 (2.85), 0.007 (6.27), 0.009 (1.14),0.146 (0.86), 0.948 (7.98), 0.966 (16.00), 0.985 (7.56), 1.146 (0.53),1.169 (1.42), 1.243 (0.90), 1.598 (1.25), 1.617 (1.59), 1.624 (1.49),1.633 (1.96), 1.642 (1.69), 1.652 (1.62), 1.659 (1.78), 1.677 (1.33),1.851 (1.53), 1.860 (1.67), 1.869 (1.65), 1.879 (1.82), 1.885 (1.52),1.895 (1.39), 1.904 (1.20), 1.913 (1.01), 2.322 (0.87), 2.327 (1.15),2.332 (0.91), 2.366 (1.73), 2.403 (0.53), 2.416 (0.72), 2.424 (0.89),2.518 (4.50), 2.521 (4.24), 2.665 (0.61), 2.669 (0.87), 2.674 (0.60),2.709 (1.31), 3.040 (1.83), 3.324 (1.08), 3.327 (0.74), 3.624 (1.00),4.334 (0.70), 4.424 (0.70), 4.710 (0.98), 4.726 (1.44), 4.749 (1.41),6.984 (2.44), 7.007 (2.46), 7.304 (1.49), 7.326 (2.78), 7.342 (1.53),7.347 (1.53), 7.547 (1.66), 7.554 (1.78), 7.573 (2.58), 7.576 (2.63),7.595 (1.85), 7.602 (1.70), 7.808 (1.96), 7.816 (1.71), 7.823 (1.76),7.830 (1.89), 8.309 (3.08), 8.331 (3.03), 8.641 (5.53), 8.647 (5.09),10.458 (4.33), 10.482 (4.24). 104 rac-1-(2,4-Difluorophenyl)-7-[(2-fluoroethyl)(methyl)amino]-4-oxo-N-[1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide  

  (70% of theory) LC-MS (Method 3): R_(t) = 2.80 min MS (ESpos): m/z =487.1 [M + H]⁺ ¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.150 (1.38), −0.009(11.87), 0.007 (11.12), 0.146 (1.29), 0.948 (7.35), 0.966 (16.00), 0.985(7.63), 1.148 (0.57), 1.169 (1.25), 1.259 (0.90), 1.599 (1.06), 1.617(1.43), 1.624 (1.37), 1.633 (1.78), 1.642 (1.54), 1.651 (1.62), 1.659(1.74), 1.677 (1.47), 1.850 (1.25), 1.860 (1.53), 1.868 (1.43), 1.879(1.72), 1.894 (1.21), 1.914 (1.00), 2.327 (1.59), 2.331 (1.26), 2.365(2.15), 2.669 (1.51), 2.709 (1.91), 3.034 (1.72), 3.622 (1.03), 4.346(0.78), 4.427 (0.72), 4.731 (1.51), 4.754 (1.38), 6.984 (2.40), 7.008(2.40), 7.305 (1.50), 7.320 (2.79), 7.340 (1.60), 7.547 (1.68), 7.554(1.91), 7.573 (2.75), 7.595 (1.78), 7.602 (1.60), 7.808 (1.96), 7.830(1.90), 8.309 (3.31), 8.331 (3.10), 8.641 (6.21), 8.647 (5.57), 10.458(4.46), 10.482 (4.09). 105rac-1-(2,4-Difluorophenyl)-7-[(2-fluoroethyl)(methyl)amino]-4-oxo-N-[1,1,1-trifluoropropan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide  

  Workup: Add water/1M aqueous hydrochloric acid and filter off theprecipitate. (72% of theory) LC-MS (Method 2): R_(t) = 2.71 min MS(ESpos): m/z = 473.1 [M + H]⁺ ¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.150(0.75), −0.009 (9.82), 0.007 (6.09), 0.146 (0.75), 1.169 (1.04), 1.242(1.12), 1.259 (1.01), 1.272 (0.81), 1.322 (0.61), 1.339 (0.97), 1.363(16.00), 1.381 (15.67), 2.322 (0.61), 2.327 (0.85), 2.331 (0.61), 2.365(1.09), 2.665 (0.64), 2.669 (0.83), 2.674 (0.59), 2.709 (1.06), 2.890(0.61), 3.037 (1.81), 3.632 (0.98), 4.338 (0.71), 4.435 (0.72), 4.863(1.19), 4.883 (1.81), 4.904 (1.75), 4.923 (1.05), 6.982 (2.40), 7.005(2.44), 7.300 (1.48), 7.304 (1.57), 7.321 (2.73), 7.326 (2.74), 7.343(1.50), 7.347 (1.52), 7.547 (1.47), 7.554 (1.57), 7.573 (2.53), 7.595(1.57), 7.602 (1.39), 7.781 (1.24), 7.796 (1.44), 7.804 (1.47), 7.812(1.50), 7.827 (1.27), 8.300 (3.07), 8.323 (2.86), 8.634 (5.56), 8.639(4.62), 10.509 (2.89), 10.532 (2.72). 1061-(2,4-Difluorophenyl)-7-[(2-fluoroethyl)(methyl)amino]-4-oxo-N-[1,1,1-trifluoropentan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide  

  Workup: Add water/1M aqueous hydrochloric acid and filter off theprecipitate. (83% of theory) LC-MS (Method 2): R_(t) = 2.93 min MS(ESpos): m/z = 501.1 [M + H]⁺ ¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.009(3.94), 0.007 (3.37), 0.881 (0.92), 0.893 (7.30), 0.912 (16.00), 0.930(8.22), 1.168 (1.40), 1.243 (1.28), 1.259 (1.19), 1.273 (1.01), 1.298(0.80), 1.316 (1.26), 1.322 (1.31), 1.338 (1.79), 1.353 (1.95), 1.371(1.81), 1.389 (1.27), 1.409 (1.09), 1.430 (1.25), 1.442 (1.60), 1.462(1.43), 1.594 (0.71), 1.606 (0.76), 1.621 (1.05), 1.628 (1.78), 1.640(1.35), 1.654 (1.83), 1.667 (1.25), 1.677 (0.98), 1.690 (0.77), 1.739(1.00), 1.748 (1.15), 1.765 (1.62), 1.772 (1.74), 1.780 (1.38), 1.790(1.48), 1.796 (1.09), 2.523 (0.94), 2.890 (0.90), 3.040 (1.77), 3.616(0.94), 3.626 (0.96), 4.324 (0.71), 4.443 (0.69), 4.773 (0.86), 4.792(1.43), 4.816 (1.45), 4.834 (0.81), 6.983 (2.47), 7.006 (2.53), 7.298(1.43), 7.302 (1.51), 7.319 (2.85), 7.324 (2.87), 7.340 (1.55), 7.345(1.59), 7.545 (1.73), 7.551 (1.83), 7.570 (2.71), 7.574 (2.69), 7.593(1.86), 7.600 (1.73), 7.790 (1.08), 7.810 (2.21), 7.828 (2.23), 7.847(0.94), 8.305 (3.19), 8.327 (3.09), 8.641 (6.69), 10.453 (4.58), 10.477(4.39). 107rac-1-(2,4-Difluorophenyl)-7-[(2-fluoroethyl)(methyl)amino]-4-oxo-N-[1,1,1-trifluoro-4-methylpentan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide  

  Workup: Add water/1M aqueous hydrochloric acid and filter off theprecipitate. (80% of theory) LC-MS (Method 3): R_(t) = 3.04 min MS(ESpos): m/z = 515.1 [M + H]⁺ ¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.009(6.42), 0.007 (4.09), 0.883 (13.44), 0.895 (14.22), 0.941 (15.51), 0.956(16.00), 1.168 (2.55), 1.562 (3.80), 1.589 (3.13), 1.644 (4.16), 1.671(5.56), 1.698 (2.43), 2.365 (0.82), 2.669 (0.70), 2.709 (0.89), 3.040(2.45), 3.617 (1.28), 4.438 (0.95), 4.816 (1.94), 6.982 (3.12), 7.005(3.15), 7.301 (2.00), 7.322 (3.69), 7.338 (1.98), 7.542 (2.15), 7.549(2.23), 7.568 (3.47), 7.591 (2.21), 7.597 (2.11), 7.794 (1.99), 7.816(3.88), 7.831 (3.84), 7.853 (1.76), 8.302 (4.18), 8.324 (4.00), 8.648(13.72), 10.450 (5.71), 10.474 (5.53). 1081-(2,4-Difluorophenyl)-7-[(2-fluoroethyl)(methyl)amino]-4-oxo-N-[1,1,1-trifluoro-3-methylbutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide  

  Workup: Add water/1M aqueous hydrochloric acid and filter off theprecipitate. (99% of theory) LC-MS (Method 1): R_(t) = 1.22 min MS(ESpos): m/z = 501.3 [M + H]⁺ ¹H-NMR (400 MHz, CDCl3) δ [ppm]: −0.000(0.10), 0.016 (0.10), 0.077 (0.05), 1.061 (0.15), 1.079 (0.15), 1.136(0.13), 1.153 (0.13), 1.587 (16.00), 2.285 (0.01), 2.302 (0.02), 2.312(0.02), 2.329 (0.01), 2.450 (0.03), 2.794 (0.03), 2.892 (0.13), 2.965(0.16), 3.144 (0.11), 3.612 (0.01), 3.641 (0.01), 4.309 (0.02), 4.419(0.02), 4.783 (0.02), 4.806 (0.01), 6.711 (0.09), 6.734 (0.09), 7.006(0.04), 7.022 (0.02), 7.043 (0.05), 7.063 (0.05), 7.085 (0.01), 7.352(0.02), 7.366 (0.02), 7.374 (0.03), 7.387 (0.03), 7.394 (0.02), 7.409(0.01), 7.529 (0.04), 8.025 (0.02), 8.490 (0.08), 8.513 (0.07), 8.697(0.13), 10.550 (0.02), 10.575 (0.02). 1091-(2,4-Difluorophenyl)-7-[(2-fluoroethyl)(methyl)amino]-4-oxo-N-[1-(trifluoromethyl)cyclopropyl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide  

  Workup: Add water/1M aqueous hydrochloric acid and filter off theprecipitate. (75% of theory) LC-MS (Method 1): R_(t) = 1.11 min MS(ESpos): m/z = 485.3 [M + H]⁺ ¹H-NMR (400 MHz, CDCl₃) δ [ppm]: 0.001(0.18), 0.017 (0.17), 0.078 (0.11), 1.223 (0.13), 1.237 (0.14), 1.267(0.05), 1.355 (0.04), 1.371 (0.06), 1.392 (0.32), 1.417 (0.04), 1.573(16.00), 2.449 (0.06), 2.794 (0.06), 2.893 (0.04), 2.965 (0.05), 3.140(0.36), 3.607 (0.05), 3.620 (0.05), 3.633 (0.05), 4.307 (0.06), 4.419(0.06), 6.705 (0.26), 6.728 (0.27), 7.006 (0.08), 7.016 (0.07), 7.030(0.07), 7.039 (0.18), 7.048 (0.04), 7.059 (0.19), 7.080 (0.06), 7.339(0.06), 7.353 (0.07), 7.361 (0.09), 7.375 (0.09), 7.528 (0.06), 8.449(0.23), 8.472 (0.22), 8.673 (0.43), 10.596 (0.15). 1101-(2,4-Difluorophenyl)-N-(4-fluorobicyclo[2.2.2]oct-1-yl)-7-[(2-fluoroethyl)(methyl)amino]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide  

  Workup: Add water/1M aqueous hydrochloric acid and filter off theprecipitate. (88% of theory) LC-MS (Method 1): R_(t) = 1.18 min MS(ESpos): m/z = 503.3 [M + H]⁺ ¹H-NMR (400 MHz, CDCl3) δ [ppm]: 0.000(0.20), 0.017 (0.21), 0.078 (0.12), 1.041 (0.05), 1.576 (16.00), 1.937(0.17), 1.952 (0.31), 1.967 (0.31), 1.978 (0.34), 1.992 (0.22), 2.235(0.38), 2.246 (0.30), 2.257 (0.35), 2.276 (0.29), 2.450 (0.07), 2.602(0.03), 2.635 (0.12), 2.639 (0.07), 2.641 (0.05), 2.644 (0.05), 2.794(0.06), 2.965 (0.03), 3.132 (0.41), 3.565 (0.04), 3.602 (0.05), 3.613(0.05), 3.627 (0.04), 3.667 (0.04), 4.298 (0.06), 4.415 (0.06), 6.690(0.33), 6.713 (0.33), 6.998 (0.05), 7.006 (0.14), 7.018 (0.07), 7.026(0.24), 7.034 (0.05), 7.046 (0.25), 7.053 (0.08), 7.066 (0.06), 7.075(0.04), 7.256 (0.06), 7.260 (0.13), 7.281 (0.08), 7.290 (0.04), 7.294(0.03), 7.325 (0.07), 7.339 (0.08), 7.347 (0.10), 7.361 (0.09), 7.382(0.05), 7.529 (0.08), 8.439 (0.32), 8.462 (0.30), 8.618 (0.60), 9.956(0.16). 111 1-(2,4-Difluorophenyl)-7-[(2-fluoroethyl)(methyl)amino]-N-(1,1,1,3,3,3-hexafluoropropan-2-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide  

  (17% of theory) LC-MS (Method 1): R_(t) = 1.23 min MS (ESpos): m/z =527.1 [M + H]⁺ ¹H-NMR (400 MHz, CDCl₃) δ [ppm]: 0.002 (0.57), 0.018(0.49), 0.079 (0.13), 1.557 (16.00), 2.450 (0.09), 2.794 (0.09), 3.151(0.37), 3.613 (0.07), 3.648 (0.07), 4.305 (0.07), 4.432 (0.06), 5.309(0.16), 5.568 (0.07), 5.586 (0.08), 5.593 (0.07), 5.603 (0.06), 5.611(0.09), 5.628 (0.07), 6.733 (0.46), 6.756 (0.47), 7.006 (0.13), 7.032(0.08), 7.039 (0.11), 7.053 (0.09), 7.060 (0.30), 7.081 (0.32), 7.088(0.10), 7.100 (0.08), 7.357 (0.09), 7.372 (0.11), 7.379 (0.13), 7.394(0.13), 7.529 (0.14), 8.481 (0.36), 8.503 (0.35), 8.689 (0.72), 11.267(0.13), 11.293 (0.12).

Example 1127-[(2,2-Difluoroethyl)(methyl)amino]-1-(2,4-difluorophenyl)-4-oxo-N-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

278 mg (0.7 mmol) of the compound from example 48A were initiallycharged in 7.9 ml of DMF, 321 mg (0.84 mmol) of HATU and 291 mg (2.3mmol) of DIPEA were added, and the mixture was stirred at 20° C. for 30minutes. Then 149 mg (1.0 mmol) of 1-adamantanamine were added and themixture was stirred at 20° C. for 1 hour. Subsequently, 1 ml of 1 Maqueous hydrochloric acid was added and the mixture was purified viapreparative HPLC (eluent: acetonitrile/water gradient with 0.1% formicacid). This gave 65 mg (18% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.35 min; m/z=529.2 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 1.669 (7.89), 1.946 (0.40), 1.983(0.31), 2.055 (16.00), 3.077 (0.90), 3.157 (2.88), 3.170 (2.96), 3.725(0.36), 4.056 (0.31), 4.069 (0.86), 4.082 (0.84), 4.095 (0.30), 6.993(0.69), 7.016 (0.72), 7.297 (0.40), 7.319 (0.79), 7.336 (0.55), 7.540(0.45), 7.547 (0.47), 7.569 (0.76), 7.589 (0.47), 7.595 (0.45), 7.770(0.42), 7.786 (0.53), 7.792 (0.85), 7.807 (0.85), 7.814 (0.51), 7.829(0.39), 8.339 (1.00), 8.361 (0.98), 8.531 (3.55), 9.880 (2.28).

In analogy to Example 112, the example compounds shown in Table 13 wereprepared by reacting the compound from Example 48A with the appropriateamines (or salts thereof) under the reaction conditions described.Differences are specified in the respective examples.

TABLE 13 Ex. Analytical data 113rac-7-[(2,2-Difluoroethyl)(methyl)amino]-1-(2,4-difluorophenyl)-4-oxo-N-[1,1,1-trifluoropropan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide  

  (6% of theory) LC-MS (Method 1): R_(t) = 1.15 min MS (ESpos): m/z =491.3 [M + H]⁺ ¹H-NMR (500 MHz, DMSO-d₆) δ [ppm]: −0.120 (1.57), −0.007(16.00), 0.006 (12.71), 0.116 (1.53), 1.235 (0.81), 1.368 (14.07), 1.382(14.02), 2.361 (1.27), 2.635 (1.20), 3.101 (1.58), 3.725 (0.75), 4.890(1.59), 4.907 (1.60), 5.753 (2.66), 7.038 (1.51), 7.311 (1.38), 7.328(2.64), 7.340 (1.37), 7.559 (1.33), 7.577 (2.44), 7.597 (1.28), 7.790(1.10), 7.802 (1.56), 7.820 (1.63), 7.833 (1.19), 8.362 (2.37), 8.380(2.31), 8.672 (5.13), 8.679 (4.44), 10.466 (2.23), 10.483 (2.24). 114rac-7-[(2,2-Difluoroethyl)(methyl)amino]-1-(2,4-difluorophenyl)-4-oxo-N-[1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide  

  (92% of theory) LC-MS (Method 1): R_(t) = 1.19 min MS (ESpos): m/z =505.3 [M + H]⁺ ¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.009 (9.63), 0.007(5.71), 0.949 (7.95), 0.968 (16.00), 0.986 (7.83), 1.168 (1.61), 1.233(1.29), 1.602 (1.28), 1.620 (1.68), 1.627 (1.58), 1.637 (1.99), 1.645(1.79), 1.655 (1.61), 1.662 (1.90), 1.680 (1.38), 1.853 (1.46), 1.862(1.53), 1.871 (1.72), 1.881 (1.90), 1.897 (1.44), 1.907 (1.21), 1.916(1.03), 2.327 (1.14), 2.365 (1.46), 2.669 (0.91), 2.709 (1.20), 2.730(1.72), 2.890 (2.25), 3.091 (5.58), 3.217 (0.83), 3.709 (1.38), 4.739(1.64), 4.754 (1.48), 7.038 (2.31), 7.060 (2.27), 7.307 (1.80), 7.328(3.19), 7.344 (1.75), 7.550 (1.92), 7.556 (2.06), 7.576 (3.05), 7.598(1.88), 7.605 (1.79), 7.792 (1.12), 7.814 (2.41), 7.837 (2.18), 8.368(3.55), 8.390 (3.37), 8.680 (6.43), 8.686 (5.75), 10.412 (4.34), 10.436(4.22). 115 7-[(2,2-Difluoroethyl)(methyl)amino]-1-(2,4-difluorophenyl)-N-[1,1,1,3,3,3-hexafluoropropan-2-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide  

  (17% of theory) LC-MS (Method 1): R_(t) = 1.24 min MS (ESpos): m/z =545.0 [M + H]⁺ ¹H-NMR (400 MHz, CDCl₃) δ [ppm]: 1.269 (0.10), 1.557(16.00), 2.054 (0.15), 3.190 (1.17), 3.597 (0.09), 3.667 (0.09), 5.611(0.17), 6.766 (0.51), 6.789 (0.52), 7.065 (0.14), 7.083 (0.36), 7.102(0.33), 7.120 (0.12), 7.350 (0.12), 7.371 (0.15), 7.385 (0.17), 8.536(0.49), 8.558 (0.47), 8.723 (0.89), 11.191 (0.17), 11.215 (0.18).

Example 1161-(2,4-Difluorophenyl)-7-[4-hydroxy-4-(hydroxymethyl)piperidin-1-yl]-4-oxo-N-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

30 mg (0.07 mmol) of the compound from example 58A were initiallycharged in 0.8 ml of DMF, 32 mg (0.08 mmol) of HATU and 29 mg (0.22mmol) of DIPEA were added, and the mixture was stirred at 20° C. for 30minutes. Then 15 mg (0.1 mmol) of 1-adamantanamine were added and themixture was stirred at 20° C. for 2 hours. Subsequently, the mixture waspurified via preparative HPLC (eluent: acetonitrile/water gradient with0.1% formic acid). This gave 6 mg (15% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.14 min; m/z=565.2 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.150 (0.51), −0.009 (4.42), 0.007(3.91), 0.146 (0.50), 1.146 (0.38), 1.234 (0.81), 1.322 (0.81), 1.450(0.78), 1.670 (7.49), 2.055 (16.00), 2.327 (0.82), 2.365 (1.03), 2.669(0.87), 2.709 (1.05), 3.083 (0.65), 3.136 (2.56), 3.150 (2.63), 3.899(0.89), 4.287 (2.59), 4.550 (1.22), 5.753 (5.06), 7.062 (1.93), 7.085(1.95), 7.302 (0.43), 7.324 (0.82), 7.348 (0.44), 7.553 (0.53), 7.576(0.76), 7.595 (0.52), 7.602 (0.53), 7.760 (0.50), 7.781 (1.00), 7.796(1.00), 7.818 (0.47), 8.225 (2.67), 8.248 (2.48), 8.468 (5.33), 9.938(2.87).

Example 1171-(2,4-Difluorophenyl)-7-[(3R)-3-(hydroxymethyl)morpholin-4-yl]-4-oxo-N-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

117 mg (0.28 mmol) of the compound from example 53A were initiallycharged in 3.2 ml of DMF, 128 mg (0.34 mmol) of HATU and 116 mg (0.9mmol) of DIPEA were added, and the mixture was stirred at 20° C. for 30minutes. Then 60 mg (0.4 mmol) of 1-adamantanamine were added and themixture was stirred at 20° C. for 2 hours. Subsequently, 1 ml of 1 Maqueous hydrochloric acid was added and the mixture was purified viapreparative HPLC (eluent: acetonitrile/water gradient with 0.1% formicacid). This gave 24 mg (15% of theory) of the title compound.

LC-MS (Method 1): Rt=1.18 min; m/z=551.2 [M+H]⁺.

¹H-NMR (400 MHz, CDCl₃) δ [ppm]: 0.001 (0.73), 0.017 (0.73), 1.233(2.05), 1.430 (0.33), 1.562 (16.00), 1.693 (0.38), 1.724 (1.25), 1.745(1.30), 1.775 (0.35), 2.120 (1.10), 2.180 (3.88), 3.262 (0.20), 3.537(0.28), 3.564 (0.26), 3.594 (0.26), 3.780 (0.43), 3.949 (0.23), 4.028(0.38), 4.059 (0.53), 5.309 (0.70), 6.568 (0.24), 6.764 (0.32), 6.787(0.33), 7.006 (0.26), 7.040 (0.58), 7.060 (0.66), 7.078 (0.27), 7.375(0.24), 7.529 (0.23), 8.470 (1.03), 8.493 (0.99), 8.650 (0.95), 9.856(0.49).

Example 118rac-1-(2,4-Difluorophenyl)-7-[2-(hydroxymethyl)morpholin-4-yl]-4-oxo-N-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

60 mg (0.14 mmol) of the compound from example 51A were initiallycharged in 1.6 ml of DMF, 66 mg (0.17 mmol) of HATU and 60 mg (0.46mmol) of DIPEA were added, and the mixture was stirred at 20° C. for 30minutes. Then 30 mg (0.2 mmol) of 1-adamantanamine were added and themixture was stirred at 20° C. for 2 hours. Subsequently, 1 ml of 1 Maqueous hydrochloric acid was added and the mixture was purified viapreparative HPLC (eluent: acetonitrile/water gradient with 0.1% formicacid). This gave 28 mg (35% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.18 min; m/z=551.2 [M+H]⁺.

¹H-NMR (400 MHz, CDCl₃) δ [ppm]: −0.139 (0.05), 0.002 (0.46), 0.018(0.36), 0.079 (0.09), 0.156 (0.04), 1.233 (0.14), 1.251 (0.34), 1.269(0.70), 1.287 (0.34), 1.560 (16.00), 1.693 (0.12), 1.724 (0.41), 1.745(0.42), 1.776 (0.12), 1.830 (0.08), 2.054 (1.26), 2.121 (0.37), 2.181(1.27), 2.450 (0.04), 2.865 (0.05), 2.886 (0.05), 3.003 (0.05), 3.037(0.05), 3.568 (0.12), 3.580 (0.12), 3.595 (0.15), 3.609 (0.15), 3.624(0.10), 3.651 (0.07), 3.907 (0.10), 3.941 (0.14), 3.957 (0.14), 3.986(0.13), 4.105 (0.10), 4.123 (0.29), 4.140 (0.28), 4.159 (0.09), 6.746(0.31), 6.769 (0.32), 7.006 (0.14), 7.031 (0.21), 7.051 (0.21), 7.069(0.07), 7.349 (0.08), 7.364 (0.08), 7.371 (0.11), 7.384 (0.10), 7.392(0.06), 7.406 (0.05), 7.529 (0.10), 8.469 (0.34), 8.492 (0.33), 8.659(0.60), 9.865 (0.20).

Example 119rac-1-(2,4-Difluorophenyl)-7-(3-hydroxy-3-methylpiperidin-1-yl)-4-oxo-N-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

100 mg (0.23 mmol) of the compound from example 54A were initiallycharged in 2.6 ml of DMF, 103 mg (0.3 mmol) of HATU and 94 mg (0.73mmol) of DIPEA were added, and the mixture was stirred at 20° C. for 30minutes. Then 48 mg (0.32 mmol) of 1-adamantanamine were added and themixture was stirred at 20° C. for 2 hours. Subsequently, the mixture wasadjusted to pH 7 with 1 M aqueous hydrochloric acid and purified viapreparative HPLC (eluent: acetonitrile/water gradient with 0.1% formicacid). This gave 110 mg (88% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.28 min; m/z=549.4 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.009 (1.67), 0.007 (1.02), 0.992(1.31), 1.017 (1.70), 1.086 (0.32), 1.094 (0.32), 1.104 (0.31), 1.146(0.33), 1.168 (1.13), 1.236 (0.84), 1.269 (0.74), 1.521 (1.16), 1.584(0.75), 1.615 (0.51), 1.669 (7.59), 1.746 (0.53), 1.826 (0.43), 2.053(16.00), 2.366 (0.23), 2.523 (0.75), 2.689 (0.26), 2.709 (0.23), 2.730(1.08), 2.890 (1.46), 3.085 (0.20), 3.150 (0.25), 3.228 (0.50), 3.263(0.70), 3.407 (0.23), 3.615 (0.34), 4.366 (0.89), 4.379 (1.15), 7.021(1.80), 7.044 (1.80), 7.305 (0.43), 7.324 (0.76), 7.343 (0.41), 7.547(0.47), 7.554 (0.49), 7.572 (0.73), 7.595 (0.44), 7.602 (0.39), 7.756(0.31), 7.772 (0.59), 7.793 (0.57), 8.185 (2.02), 8.208 (1.86), 8.453(4.93), 8.464 (0.25), 9.935 (0.21), 9.957 (2.41).

Example 1207-[(2,2-Difluoroethyl)amino]-1-(2,4-difluorophenyl)-4-oxo-N-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

130 mg (0.23 mmol, 67% purity) of the compound from example 49A wereinitially charged in 2.6 ml of DMF, 105 mg (0.28 mmol) of HATU and 95 mg(0.73 mmol) of DIPEA were added, and the mixture was stirred at 20° C.for 30 minutes. Then 49 mg (0.32 mmol) of 1-adamantanamine were addedand the mixture was stirred at 20° C. for 2 hours. Subsequently, 1 ml of1 M aqueous hydrochloric acid was added and the mixture was purified viapreparative HPLC (eluent: acetonitrile/water gradient with 0.1% formicacid). This gave 99 mg (84% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.28 min; m/z=515.3 [M+H]⁺.

¹H-NMR (400 MHz, CDCl₃) δ [ppm]: 0.002 (1.20), 0.018 (1.39), 0.921(0.24), 0.935 (0.24), 1.557 (16.00), 1.694 (0.36), 1.725 (1.30), 1.746(1.36), 1.778 (0.36), 2.054 (0.23), 2.122 (1.14), 2.182 (4.00), 3.495(1.71), 3.507 (1.69), 3.529 (0.20), 3.540 (0.21), 5.195 (0.31), 5.542(0.21), 5.672 (0.22), 5.683 (0.42), 5.693 (0.20), 5.824 (0.20), 6.561(1.16), 6.583 (1.18), 7.006 (0.25), 7.033 (0.30), 7.048 (0.53), 7.053(0.54), 7.067 (0.57), 7.072 (0.46), 7.085 (0.26), 7.259 (0.44), 7.342(0.24), 7.356 (0.27), 7.363 (0.33), 7.376 (0.36), 7.385 (0.24), 7.398(0.20), 7.529 (0.25), 8.441 (1.07), 8.463 (1.04), 8.678 (1.99), 9.832(0.56).

In analogy to Example 120, the example compounds shown in Table 14 wereprepared by reacting the compound from Example 49A with the appropriateamines (or salts thereof) under the reaction conditions described.Differences are specified in the respective examples.

TABLE 14 Ex. Analytical data 121rac-7-[(2,2-Difluoroethyl)amino]-1-(2,4- LC-MS (Method 1): R_(t) = 1.06min difluorophenyl)-4-oxo-N-[1,1,1-trifluoropro- MS (ESpos): m/z = 477.2[M + H]⁺ pan-2-yl]-1,4-dihydro-1,8-naphthyridine-3- ¹H-NMR (400 MHz,CDCl₃) δ [ppm]: 0.017 carboxamide (1.03), 0.079 (0.26), 1.251 (0.34),1.269

(0.70), 1.287 (0.39), 1.451 (6.74), 1.469 (6.79), 1.568 (16.00), 2.054(1.31), 2.451 (0.23), 3.499 (0.63), 3.536 (0.64), 4.122 (0.29), 4.140(0.28), 4.899 (0.41), 4.918 (0.64), 4.937 (0.63), 4.955 (0.39), 5.279(1.13), 5.309 (0.61), 5.542 (0.54), 5.673 (0.56), 5.683 (1.08), 5.693(0.54), 5.824 (0.52), 6.593 (3.50), 6.615 (3.54), 7.006 (0.26), 7.049(0.54), 7.056 (0.78), 7.075 (2.30), 7.094 (2.15), 7.112 (0.69), 7.377(0.78), 7.398 (0.72), 7.529 (0.24), 8.444 (3.15), 8.466 (3.09), 8.713(3.35), 10.386 (0.98), 10.410 (0.97). 122rac-7-[(2,2-Difluoroethyl)amino]-1-(2,4- LC-MS (Method 1): R_(t) = 1.11min difluorophenyl)-4-oxo-N-[1,1,1-trifluorobu- MS (ESpos): m/z = 491.2[M + H]⁺ tan-2-yl]-1,4-dihydro-1,8-naphthyridine-3- ¹H-NMR (400 MHz,CDCl₃) δ [ppm]: 0.001 carboxamide (0.67), 0.017 (0.70), 0.079 (0.19),1.055

(0.55), 1.074 (1.22), 1.092 (0.61), 1.563 (16.00), 1.704 (0.09), 1.723(0.11), 1.730 (0.10), 1.740 (0.14), 1.748 (0.12), 1.758 (0.12), 1.765(0.14), 1.784 (0.11), 1.936 (0.09), 1.947 (0.10), 1.954 (0.11), 1.966(0.11), 1.982 (0.09), 2.449 (0.13), 2.794 (0.14), 3.507 (0.13), 3.538(0.12), 4.751 (0.11), 4.761 (0.10), 4.769 (0.10), 4.779 (0.11), 5.259(0.11), 5.272 (0.18), 5.309 (0.26), 5.544 (0.10), 5.674 (0.11), 5.685(0.21), 5.695 (0.11), 5.825 (0.11), 6.594 (0.73), 6.616 (0.76), 7.006(0.16), 7.050 (0.10), 7.056 (0.14), 7.076 (0.41), 7.095 (0.35), 7.101(0.21), 7.113 (0.12), 7.365 (0.12), 7.386 (0.15), 7.400 (0.16), 7.406(0.12), 7.529 (0.16), 8.450 (0.69), 8.471 (0.67), 8.722 (0.95), 10.309(0.19), 10.332 (0.19). 123 7-[(2,2-Difluoroethyl)amino]-1-(2,4-difluoro-LC-MS (Method 1): R_(t) = 1.07 minphenyl)-4-oxo-N-[(2R)-1,1,1-trifluorobutan- MS (ESpos): m/z = 491.2 [M +H]⁺ 2-yl]-1,4-dihydro-1,8-naphthyridine-3-car- ¹H-NMR (400 MHz, DMSO-d₆)δ [ppm]: boxamide −0.150 (0.74), −0.009 (10.07), 0.007 (5.25),

0.145 (0.82), 0.944 (7.49), 0.963 (16.00), 0.981 (7.84), 1.156 (1.80),1.174 (3.56), 1.192 (1.78), 1.597 (1.15), 1.615 (1.63), 1.623 (1.41),1.632 (1.89), 1.641 (1.58), 1.650 (1.56), 1.658 (1.75), 1.676 (1.37),1.849 (1.38), 1.859 (1.62), 1.867 (1.55), 1.877 (1.76), 1.883 (1.53),1.894 (1.40), 1.903 (1.14), 1.913 (0.95), 1.987 (6.41), 2.327 (0.95),2.365 (0.89), 2.558 (0.69), 2.664 (0.75), 2.669 (1.03), 2.709 (0.91),3.402 (2.56), 4.020 (1.51), 4.038 (1.49), 4.732 (1.51), 4.746 (1.41),5.640 (0.74), 5.779 (1.39), 5.922 (0.72), 6.782 (4.45), 6.805 (4.51),7.305 (1.56), 7.327 (2.88), 7.343 (1.55), 7.549 (1.71), 7.556 (1.80),7.575 (2.74), 7.598 (1.73), 7.604 (1.59), 7.815 (2.18), 7.824 (1.83),7.829 (1.78), 7.837 (2.02), 8.254 (6.67), 8.276 (6.39), 8.321 (1.84),8.641 (5.85), 8.646 (5.13), 10.457 (4.94), 10.481 (4.71). 1247-[(2,2-Difluoroethyl)amino]-1-(2,4-difluoro- LC-MS (Method 1): R_(t) =1.20 min phenyl)-4-oxo-N-[1,1,1-trifluoropentan-2-yl]- MS (ESpos): m/z =505.2 [M + H]⁺ 1,4-dihydro-1,8-naphthyridine-3-carbox- ¹H-NMR (400 MHz,DMSO-d₆) δ [ppm]: amide 0.005 (1.90), 0.890 (6.75), 0.909 (15.05),

0.927 (7.74), 1.156 (4.23), 1.173 (8.48), 1.191 (4.30), 1.312 (0.96),1.329 (1.40), 1.348 (1.72), 1.367 (1.56), 1.385 (1.04), 1.404 (0.88),1.424 (1.11), 1.437 (1.48), 1.457 (1.31), 1.472 (0.74), 1.592 (0.61),1.604 (0.65), 1.618 (0.92), 1.627 (1.59), 1.639 (1.22), 1.653 (1.70),1.664 (1.18), 1.676 (0.88), 1.688 (0.67), 1.737 (0.88), 1.746 (1.04),1.763 (1.53), 1.769 (1.62), 1.779 (1.26), 1.787 (1.38), 1.812 (0.55),1.987 (16.00), 3.366 (1.27), 3.403 (2.26), 3.438 (1.27), 4.001 (1.31),4.019 (3.84), 4.037 (3.80), 4.055 (1.25), 4.771 (0.78), 4.790 (1.36),4.814 (1.37), 4.832 (0.75), 5.638 (0.66), 5.780 (1.31), 5.921 (0.65),6.781 (4.18), 6.803 (4.27), 7.299 (1.29), 7.303 (1.36), 7.320 (2.62),7.325 (2.71), 7.341 (1.46), 7.346 (1.44), 7.546 (1.54), 7.553 (1.57),7.572 (2.53), 7.576 (2.52), 7.594 (1.60), 7.601 (1.51), 7.797 (1.02),7.817 (2.15), 7.835 (2.14), 7.854 (0.92), 8.250 (6.07), 8.272 (5.87),8.319 (1.69), 8.640 (6.16), 10.453 (4.66), 10.477 (4.50). 125rac-7-[(2,2-Difluoroethyl)amino]-1-(2,4- LC-MS (Method 1): R_(t) = 1.22min difluorophenyl)-4-oxo-N-[1,1,1-trifluoro-4- MS (ESpos): m/z = 519.1[M + H]⁺ methylpentan-2-yl]-1,4-dihydro-1,8-naph- ¹H-NMR (400 MHz,CDCl₃) δ [ppm]: 0.001 thyridine-3-carboxamide (0.59), 0.017 (0.56),0.954 (2.22), 0.963

(2.28), 0.970 (2.57), 0.984 (4.16), 1.001 (3.93), 1.251 (1.68), 1.269(3.42), 1.287 (1.71), 1.568 (16.00), 1.616 (0.64), 1.625 (0.38), 1.643(0.48), 1.708 (0.48), 1.719 (0.63), 1.737 (0.50), 1.747 (0.87), 1.753(0.56), 1.766 (0.35), 1.775 (0.61), 1.782 (0.64), 1.790 (0.37), 1.799(0.40), 2.054 (6.64), 3.502 (0.44), 3.538 (0.43), 3.546 (0.42), 3.553(0.36), 4.104 (0.50), 4.122 (1.47), 4.140 (1.45), 4.158 (0.48), 4.892(0.37), 4.897 (0.34), 4.916 (0.37), 5.255 (0.47), 5.270 (0.87), 5.285(0.44), 5.542 (0.38), 5.673 (0.38), 5.683 (0.74), 5.693 (0.38), 5.824(0.37), 6.592 (2.49), 6.614 (2.55), 7.051 (0.40), 7.071 (1.29), 7.091(1.19), 7.109 (0.35), 7.364 (0.49), 7.379 (0.56), 7.386 (0.68), 7.400(0.67), 7.407 (0.44), 7.421 (0.34), 8.442 (2.11), 8.464 (2.05), 8.725(2.43), 10.256 (0.68), 10.280 (0.67). 1267-[(2,2-Difluoroethyl)amino]-1-(2,4-difluoro- LC-MS (Method 1): R_(t) =1.17 min phenyl)-N-(1,1,1,3,3,3-hexafluoropropan-2- MS (ESpos): m/z =531.2 [M + H]⁺ yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3- ¹H-NMR (400MHz, CDCl₃) δ [ppm]: 0.002 carboxamide (1.44), 0.018 (1.22), 1.251(0.71), 1.269

(1.54), 1.287 (0.74), 1.557 (16.00), 2.054 (2.72), 3.479 (0.46), 3.493(0.41), 3.501 (0.69), 3.516 (0.89), 3.528 (0.69), 3.537 (0.74), 3.547(0.81), 3.552 (0.81), 3.563 (0.70), 3.583 (0.40), 3.589 (0.39), 4.123(0.59), 4.141 (0.59), 5.294 (1.00), 5.309 (1.40), 5.544 (0.71), 5.554(0.41), 5.566 (0.63), 5.584 (0.82), 5.591 (0.71), 5.601 (0.65), 5.609(0.84), 5.626 (0.60), 5.674 (0.67), 5.685 (1.33), 5.695 (0.66), 5.825(0.65), 6.615 (4.34), 6.637 (4.44), 7.065 (0.66), 7.071 (1.01), 7.089(2.38), 7.096 (1.19), 7.108 (2.23), 7.116 (1.30), 7.126 (0.83), 7.129(0.72), 7.133 (0.46), 7.136 (0.50), 7.371 (0.88), 7.385 (0.97), 7.393(1.05), 7.407 (1.17), 7.414 (0.71), 7.428 (0.61), 8.465 (3.85), 8.486(3.76), 8.720 (6.71), 11.176 (1.18), 11.201 (1.17).

Example 127rac-1-(2,4-Difluorophenyl)-7-[2-(hydroxymethyl)pyrrolidin-1-yl]-4-oxo-N-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

100 mg (0.25 mmol) of the compound from example 52A were initiallycharged in 2.8 ml of DMF, 114 mg (0.3 mmol) of HATU and 103 mg (0.8mmol) of DIPEA were added, and the mixture was stirred at 20° C. for 30minutes. Then 49 mg (0.32 mmol) of 1-adamantanamine were added and themixture was stirred at 20° C. for 2 hours. Subsequently, 1 ml of 1 Maqueous hydrochloric acid was added and the mixture was purified viapreparative HPLC (eluent: acetonitrile/water gradient with 0.1% formicacid). This gave 76 mg (57% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.27 min; m/z=535.3 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.150 (1.22), −0.009 (14.65), 0.007(10.98), 0.018 (0.98), 0.025 (0.54), 0.058 (0.18), 0.083 (0.13), 0.146(1.22), 1.146 (0.44), 1.168 (0.21), 1.225 (0.57), 1.243 (2.78), 1.259(2.59), 1.273 (1.71), 1.355 (0.26), 1.586 (0.40), 1.670 (7.56), 1.752(0.51), 1.827 (0.87), 1.926 (0.77), 2.055 (16.00), 2.137 (0.14), 2.274(0.14), 2.322 (0.73), 2.327 (0.95), 2.332 (0.68), 2.365 (1.41), 2.390(0.22), 2.523 (4.43), 2.559 (0.82), 2.669 (0.94), 2.674 (0.67), 2.689(0.41), 2.709 (1.31), 2.730 (0.71), 2.890 (1.05), 3.129 (0.49), 3.139(0.52), 3.147 (0.50), 3.157 (0.47), 3.427 (0.20), 3.466 (0.24), 3.600(0.16), 3.616 (0.21), 3.625 (0.18), 3.958 (0.15), 4.340 (0.14), 4.462(0.13), 6.705 (0.26), 6.867 (0.15), 7.278 (0.46), 7.299 (0.76), 7.317(0.42), 7.547 (0.39), 7.731 (0.37), 7.753 (0.65), 7.769 (0.65), 7.889(0.12), 7.954 (0.13), 8.019 (0.12), 8.239 (0.99), 8.261 (0.85), 8.471(2.45), 9.962 (2.29)

Example 1281-(2,4-Difluorophenyl)-4-oxo-7-(2-oxo-1,3-oxazolidin-3-yl)-N-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

28 mg (0.04 mmol, 59% purity (HPLC)) of the compound from example 61Awere initially charged in 1 ml of DMF, 24 mg (0.06 mmol) of HATU and 18mg (0.14 mmol) of DIPEA were added, and the mixture was stirred at 20°C. for 30 minutes. Then 12 mg (0.08 mmol) of 1-adamantanamine were addedand the mixture was stirred at 23° C. for 9 hours. The mixture was leftto stand for 13 h and then purified via preparative HPLC (eluent:acetonitrile/water gradient with 0.1% formic acid). This gave 12 mg (54%of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.30 min; m/z=521.2 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.150 (1.16), −0.009 (10.40), 0.007(9.44), 0.016 (0.60), 0.021 (0.38), 0.146 (1.19), 1.680 (5.04), 2.072(16.00), 2.322 (0.58), 2.327 (0.93), 2.331 (0.68), 2.366 (1.10), 2.520(1.96), 2.523 (2.04), 2.525 (1.76), 2.558 (0.72), 2.560 (0.57), 2.563(0.46), 2.565 (0.45), 2.660 (0.41), 2.664 (0.63), 2.669 (0.93), 2.674(0.61), 2.709 (1.14), 3.285 (0.67), 3.711 (0.38), 3.730 (0.79), 3.753(0.82), 3.771 (0.39), 4.356 (0.52), 4.377 (0.83), 4.385 (0.86), 4.397(0.50), 4.405 (0.50), 7.353 (0.60), 7.565 (0.42), 7.598 (0.52), 7.613(0.40), 7.620 (0.40), 7.827 (0.41), 7.842 (0.43), 7.849 (0.71), 7.864(0.73), 7.871 (0.38), 8.265 (2.34), 8.287 (2.47), 8.678 (2.58), 8.700(2.77), 8.703 (4.30), 9.720 (1.95).

Example 1291-(2,4-Difluorophenyl)-4-oxo-7-(1,3-thiazolidin-3-yl)-N-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

200 mg (0.26 mmol) of the compound from example 59A were initiallycharged in 5.8 ml of DMF, 235 mg (0.62 mmol) of HATU and 212 mg (1.64mmol) of DIPEA were added, and the mixture was stirred at 20° C. for 30minutes. Then 109 mg (0.72 mmol) of 1-adamantanamine were added and themixture was stirred at 20° C. for 2 hours. Subsequently, the mixture waspurified via preparative HPLC (eluent: acetonitrile/water gradient with0.1% formic acid). This gave 130 mg (48% of theory) of the titlecompound.

LC-MS (Method 1): R_(t)=1.48 min; m/z=523.2 [M+H]⁺.

1H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.009 (1.08), −0.001 (16.00), 0.007(0.50), 1.672 (1.96), 1.987 (0.08), 2.058 (4.16), 3.084 (0.32), 3.099(0.63), 3.115 (0.32), 3.161 (0.22), 3.174 (0.23), 3.614 (0.33), 4.419(0.44), 6.885 (0.59), 6.907 (0.60), 7.303 (0.12), 7.319 (0.21), 7.346(0.11), 7.546 (0.14), 7.553 (0.15), 7.572 (0.20), 7.594 (0.14), 7.601(0.13), 7.775 (0.14), 7.789 (0.17), 7.796 (0.26), 7.811 (0.25), 7.833(0.12), 8.330 (0.74), 8.353 (0.68), 8.515 (1.27), 9.898 (0.67).

Example 1301-(2,4-Difluorophenyl)-7-(1,1-dioxido-1,3-thiazolidin-3-yl)-4-oxo-N-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

98 mg (0.19 mmol) of the compound from Example 129 were initiallycharged in 1.4 ml of dioxane and 0.7 ml of water, 98 mg (0.56 mmol) ofdipotassium hydrogenphosphate and 344 mg (0.56 mmol) of OXONE® wereadded, and the mixture was stirred at 23° C. for 8 h and then left tostand for 13 h. Water was added to the mixture, the precipitated solidwas filtered off and the latter was then purified via preparative HPLC(eluent: acetonitrile/water gradient with 0.1% formic acid). This gave67 mg (64% of theory) of the title compound. In addition, 12 mg (12% oftheory) of the title compound from Example 131 were obtained (foranalysis see Example 131).

LC-MS (Method 1): R_(t)=1.20 min; m/z=555.3 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.009 (1.95), 0.007 (1.22), 1.673(7.35), 2.061 (16.00), 2.072 (4.15), 3.526 (1.04), 3.544 (2.15), 3.562(1.26), 3.799 (0.98), 4.560 (1.05), 6.963 (1.49), 6.985 (1.48), 7.318(0.45), 7.340 (0.78), 7.361 (0.44), 7.564 (0.55), 7.571 (0.57), 7.590(0.76), 7.613 (0.53), 7.620 (0.49), 7.791 (0.53), 7.806 (0.64), 7.813(1.01), 7.828 (0.98), 7.835 (0.55), 7.850 (0.47), 8.420 (2.63), 8.442(2.44), 8.562 (5.10), 9.841 (2.67).

Example 1311-(2,4-Difluorophenyl)-7-(1-oxido-1,3-thiazolidin-3-yl)-4-oxo-N-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

As described in the preparation of the compound from Example 130, 98 mg(0.19 mmol) of the compound from Example 129 were used to obtain 12 mg(12% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.09 min; m/z=539.3 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.009 (2.26), 0.007 (1.41), 1.026(1.00), 1.043 (0.87), 1.234 (0.36), 1.673 (7.26), 2.061 (16.00), 2.522(1.08), 3.072 (0.45), 3.923 (0.56), 4.312 (0.41), 4.622 (0.35), 6.964(2.06), 6.986 (2.07), 7.338 (0.60), 7.578 (0.45), 7.809 (0.56), 8.177(2.22), 8.377 (2.66), 8.399 (2.45), 8.534 (4.78), 9.883 (2.63).

Example 1321-(2,4-Difluorophenyl)-7-(dimethylamino)-4-oxo-N-[(2S)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

To 100 mg (0.29 mmol) of the compound from Example 36A and 73 mg (0.72mmol) of N-methylmorpholine in 3.1 ml of DMF was added, at 0° C., 0.58ml (0.58 mmol) of isopropyl chloroformate (1 M in toluene), and themixture was stirred at 0° C. for 1 h. Then, at 0° C., 58 mg (0.38 mmol)of (R)-2,2-dimethyl-1-trifluoromethylpropylamine were added and themixture was stirred at 20° C. for 16 hours. Subsequently, the mixturewas concentrated and purified via preparative HPLC (eluent:acetonitrile/water gradient with 0.1% formic acid). This gave 20 mg (15%of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.26 min; m/z=483.2 [M+H]⁺.

1H-NMR (400 MHz, CDCl3) δ [ppm]: 0.080 (0.08), 1.174 (1.07), 1.266(0.04), 1.551 (16.00), 3.000 (0.35), 4.651 (0.04), 4.675 (0.05), 4.698(0.04), 6.669 (0.13), 6.692 (0.13), 7.006 (0.07), 7.042 (0.07), 7.061(0.07), 7.371 (0.03), 7.385 (0.04), 7.392 (0.05), 7.407 (0.04), 7.528(0.07), 8.449 (0.12), 8.472 (0.12), 8.688 (0.20), 10.742 (0.04), 10.768(0.04).

In analogy to Example 132, the example compounds shown in Table 15 wereprepared by reacting the compound from Example 36A with the appropriateamines (or salts thereof) under the reaction conditions described.Differences are specified in the respective examples.

TABLE 15 Ex. Analytical data 1331-(2,4-Difluorophenyl)-7-(dimethylamino)-4- LC-MS (Method 1): R_(t) =1.29 min oxo-N-[(2R)-1,1,1-trifluoro-4-methylpentan- MS (ESpos): m/z =483.2 [M + H]⁺ 2-yl]-1,4-dihydro-1,8-naphthyridine-3-car- ¹H-NMR (400MHz, CDCl₃) δ [ppm]: boxamide −0.139 (0.03), 0.156 (0.03), 0.958 (0.19),

0.974 (0.22), 0.983 (0.32), 0.999 (0.28), 1.266 (0.06), 1.551 (16.00),1.609 (0.06), 1.634 (0.04), 1.713 (0.03), 1.723 (0.04), 1.752 (0.04),1.787 (0.05), 3.000 (0.35), 4.894 (0.03), 6.671 (0.13), 6.694 (0.13),7.006 (0.07), 7.038 (0.08), 7.059 (0.07), 7.367 (0.04), 7.388 (0.05),7.402 (0.05), 7.424 (0.02), 7.528 (0.07), 8.415 (0.13), 8.438 (0.13),8.684 (0.18), 10.389 (0.04), 10.415 (0.04). 1341-(2,4-Difluorophenyl)-7-(dimethylamino)-4- LC-MS (Method 1): R_(t) =1.23 min oxo-N-[(2S)-1,1,1-trifluoro-3-methylbutan-2- MS (ESpos): m/z =469.2 [M + H]⁺ yl]-1,4-dihydro-1,8-naphthyridine-3-carbox- ¹H-NMR (400MHz, CDCl₃) δ [ppm]: 0.000 amide (0.22), 0.017 (0.20), 0.078 (0.13),1.062

(0.81), 1.079 (0.83), 1.137 (0.70), 1.154 (0.72), 1.265 (0.08), 1.576(16.00), 2.300 (0.10), 2.310 (0.11), 2.450 (0.07), 2.793 (0.07), 3.000(1.08), 4.789 (0.08), 6.670 (0.59), 6.693 (0.60), 7.006 (0.09), 7.023(0.11), 7.042 (0.23), 7.062 (0.21), 7.367 (0.11), 7.382 (0.13), 7.389(0.14), 7.403 (0.14), 7.425 (0.08), 7.529 (0.09), 8.444 (0.57), 8.467(0.55), 8.687 (0.79), 10.606 (0.13), 10.632 (0.12).

Example 1351-(2,4-Difluorophenyl)-4-oxo-7-(pyrrolidin-1-yl)-N-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

To 80 mg (0.22 mmol) of the compound from Example 57A and 54.5 mg (0.54mmol) of N-methylmorpholine in 2.6 ml of DMF was added, at 0° C., 0.43ml (0.43 mmol) of isopropyl chloroformate (1 M in toluene), and themixture was stirred at 0° C. for 1 h. Then, at 0° C., 42 mg (0.28 mmol)of 1-adamantanamine were added and the mixture was stirred at 20° C. for2 hours. After 12 h at 20° C., the mixture was purified via preparativeHPLC (eluent: acetonitrile/water gradient with 0.1% formic acid). Thisgave 20 mg (19% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.47 min; m/z=505.3 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ=1.67 (m, 6H), 1.74-1.99 (m, 4H), 2.06 (m,9H), 2.99-3.23 (m, 2H), 3.34-3.48 (m, 2H), 6.70 (d, 1H), 7.28-7.34 (m,1H), 7.53-7.60 (m, 1H), 7.74-7.81 (m, 1H), 8.25 (d, 1H), 8.47 (s, 1H),9.97 (br. s, 1H).

Example 1361-(2,4-Difluorophenyl)-7-(morpholin-4-yl)-4-oxo-N-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

To 80 mg (0.17 mmol, 83% purity) of the compound from Example 56A and 43mg (0.43 mmol) of N-methylmorpholine in 2 ml of DMF was added, at 0° C.,0.34 ml (0.34 mmol) of isopropyl chloroformate (1 M in toluene), and themixture was stirred at 0° C. for 1 h. Then, at 0° C., 34 mg (0.22 mmol)of 1-adamantanamine were added and the mixture was stirred at 20° C. for2 hours. The mixture was purified via preparative HPLC (eluent:acetonitrile/water gradient with 0.1% formic acid). This gave 29 mg (33%of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.47 min; m/z=521.2 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 0.000 (16.00), 1.671 (3.77), 2.055(7.92), 3.443 (1.72), 3.454 (1.40), 3.574 (1.56), 3.587 (1.91), 7.064(0.97), 7.087 (0.98), 7.301 (0.21), 7.323 (0.42), 7.340 (0.22), 7.550(0.28), 7.572 (0.40), 7.592 (0.28), 7.763 (0.25), 7.785 (0.50), 7.800(0.49), 7.821 (0.23), 8.296 (1.30), 8.318 (1.21), 8.491 (2.61), 9.897(1.31).

Example 1371-(2,4-Difluorophenyl)-7-(dimethylamino)-4-oxo-N-[(2S)-1,1,1-trifluoro-4-methylpentan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

To 100 mg (0.29 mmol) of the compound from Example 36A and 73 mg (0.72mmol) of N-methylmorpholine in 3.1 ml of DMF was added, at 0° C., 0.58ml (0.58 mmol) of isopropyl chloroformate (1 M in toluene), and themixture was stirred at 0° C. for 1 h. Then, at 0° C., 58 mg (0.38 mmol)of (S)-1,1,1-trifluoro-4-methyl-2-pentylamine were added and the mixturewas stirred at 20° C. for 16 hours. Then the mixture was purified viapreparative HPLC (eluent: acetonitrile/water gradient with 0.1% formicacid). This gave 104 mg (74% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.28 min; m/z=483.2 [M+H]⁺.

¹H-NMR (400 MHz, CDCl₃) δ [ppm]: 0.958 (4.49), 0.975 (5.14), 0.983(6.83), 0.999 (6.13), 1.266 (0.96), 1.564 (16.00), 1.609 (1.34), 1.635(0.88), 1.713 (0.67), 1.723 (0.84), 1.751 (1.06), 1.786 (1.05), 2.999(7.99), 4.919 (0.54), 6.671 (2.93), 6.693 (3.01), 7.019 (0.67), 7.039(1.67), 7.058 (1.54), 7.367 (0.65), 7.387 (0.97), 7.402 (0.99), 7.424(0.49), 8.414 (2.85), 8.437 (2.78), 8.683 (4.11), 10.391 (0.96), 10.415(0.98).

In analogy to Example 137, the example compounds shown in Table 16 wereprepared by reacting the compound from Example 36A or 60A with theappropriate amines (or salts thereof) under the reaction conditionsdescribed. Differences are specified in the respective examples.

TABLE 16 Ex. Analytical data 138 rac-1-(2,4-Difluorophenyl)-7-(dimethyl-LC-MS (Method 1): R_(t) = 1.36 min amino)-4-oxo-N-[2,2,2-trifluoro-1-(3-MS (ESpos): m/z = 517.2 [M + H]⁺methylphenyl)ethyl]-1,4-dihydro-1,8-naph- ¹H-NMR (400 MHz, DMSO-d₆) δ[ppm]: thyridine-3-carboxamide −0.009 (2.14), 0.007 (1.88), 1.387(4.58),

2.351 (16.00), 2.522 (0.44), 2.890 (0.83), 2.950 (2.67), 5.962 (0.92),5.984 (1.25), 6.006 (0.84), 6.942 (4.11), 6.965 (4.18), 7.245 (1.22),7.262 (1.92), 7.310 (0.79), 7.332 (1.20), 7.355 (7.81), 7.371 (2.23),7.391 (0.56), 7.553 (0.46), 7.573 (0.79), 7.750 (0.44), 7.769 (0.66),7.783 (0.53), 7.791 (0.49), 7.819 (0.49), 7.834 (0.47), 8.326 (4.55),8.349 (4.33), 8.424 (0.68), 8.618 (8.10), 11.425 (2.01), 11.449 (1.94).139 rac-1-(2,4-Difluorophenyl)-7-(dimethyl- LC-MS (Method 1): R_(t) =1.32 min amino)-4-oxo-N-[2,2,2-trifluoro-1-(4-fluoro- MS (ESpos): m/z =521.2 [M + H]⁺ phenyl)ethyl]-1,4-dihydro-1,8-naphthyridine- ¹H-NMR (400MHz, DMSO-d₆) δ [ppm]: 3-carboxamide 0.007 (4.07), 2.072 (1.25), 2.951(5.22),

6.091 (1.85), 6.113 (2.53), 6.134 (1.71), 6.946 (7.80), 6.969 (7.93),7.308 (6.62), 7.330 (12.46), 7.352 (6.41), 7.574 (1.76), 7.608 (4.02),7.622 (4.54), 7.641 (3.07), 7.753 (0.93), 7.768 (0.94), 7.818 (1.05),7.833 (1.00), 8.322 (8.62), 8.345 (8.23), 8.622 (16.00), 11.479 (4.76),11.503 (4.56) 140 rac-1-(2,4-Difluorophenyl)-7-(dimethyl- LC-MS (Method1): R_(t) = 1.25 min amino)-4-oxo-N-[2,2,2-trifluoro-1-(3-fluoro- MS(ESpos): m/z = 521.2 [M + H]⁺phenyl)ethyl]-1,4-dihydro-1,8-naphthyridine- ¹H-NMR (400 MHz, DMSO-d₆) δ[ppm]: 3-carboxamide −0.009 (12.35), 0.004 (4.35), 0.006 (3.57),

0.007 (5.74), 2.072 (2.45), 2.366 (0.89), 2.526 (7.91), 2.669 (0.95),2.709 (0.99), 2.954 (4.94), 6.134 (1.60), 6.156 (2.15), 6.177 (1.39),6.950 (7.54), 6.973 (7.35), 7.285 (1.95), 7.299 (3.43), 7.306 (3.99),7.321 (2.88), 7.326 (2.96), 7.413 (3.90), 7.431 (4.16), 7.528 (2.24),7.544 (3.21), 7.549 (4.29), 7.564 (4.14), 7.569 (2.98), 7.584 (2.43),7.753 (0.97), 7.769 (0.91), 7.819 (0.98), 7.835 (0.95), 8.331 (8.79),8.353 (8.26), 8.627 (16.00), 11.500 (4.07), 11.523 (3.81). 141rac-1-(2,4-Difluorophenyl)-7-(dimethyl- LC-MS (Method 1): R_(t) = 1.36min amino)-4-oxo-N-[2,2,2-trifluoro-1-(4- MS (ESpos): m/z = 517.2 [M +H]⁺ methylphenyl)ethyl]-1,4-dihydro-1,8-naph- ¹H-NMR (400 MHz, DMSO-d₆)δ [ppm]: thyridine-3-carboxamide −0.009 (5.89), 0.007 (3.81), 2.072(0.71),

2.324 (16.00), 2.523 (1.41), 2.948 (2.94), 5.962 (0.99), 5.983 (1.29),6.005 (0.83), 6.943 (4.65), 6.966 (4.56), 7.275 (4.04), 7.295 (5.29),7.326 (0.91), 7.427 (3.90), 7.447 (2.96), 7.572 (0.93), 7.753 (0.49),7.766 (0.52), 7.819 (0.53), 7.833 (0.52), 8.322 (5.43), 8.345 (5.01),8.617 (9.31), 11.420 (2.08), 11.443 (1.96). 142rac-1-(2,4-Difluorophenyl)-7-(dimethyl- LC-MS (Method 1): R_(t) = 1.24min amino)-4-oxo-N-[2,2,2-trifluoro-1-(2- MS (ESpos): m/z = 517.1 [M +H]⁺ methylphenyl)ethyl]-1,4-dihydro-1,8-naph- ¹H-NMR (400 MHz, DMSO-d₆)δ [ppm]: thyridine-3-carboxamide −0.009 (2.71), 0.007 (2.25), 2.072(2.19),

2.443 (16.00), 2.523 (0.78), 2.946 (4.02), 3.287 (0.69), 6.149 (1.47),6.170 (2.06), 6.192 (1.37), 6.937 (6.45), 6.960 (6.55), 7.291 (1.26),7.297 (1.95), 7.314 (6.35), 7.329 (4.65), 7.346 (2.90), 7.361 (2.05),7.379 (0.78), 7.460 (1.86), 7.568 (1.13), 7.739 (0.68), 7.755 (0.71),7.814 (0.75), 7.830 (0.71), 8.307 (7.18), 8.330 (6.80), 8.615 (11.47),11.459 (3.56), 11.482 (3.44). 143rac-1-(2,4-Difluorophenyl)-7-(dimethyl- LC-MS (Method 1): R_(t) = 1.35min amino)-4-oxo-N-(1,1,1-trifluoro-3-phenylpro- MS (ESpos): m /z =517.2 [M + H]⁺ pan-2-yl)-1,4-dihydro-1,8-naphthyridine-3- ¹H-NMR (400MHz, DMSO-d₆) δ [ppm]: carboxamide −0.009 (8.70), 0.007 (3.77), 2.072(2.06),

02.085 (3.79), 2.730 (7.16), 2.890 (12.47), 2.901 (7.59), 2.936 (13.83),2.963 (8.00), 3.219 (4.15), 3.246 (3.55), 5.082 (2.18), 6.915 (12.58),6.938 (12.45), 7.201 (3.83), 7.273 (8.46), 7.310 (10.19), 7.547 (3.56),7.767 (2.90), 8.268 (16.00), 8.291 (14.62), 8.479 (7.19), 8.489 (5.88),10.590 (7.45), 10.614 (6.89). 144rac-1-(2,4-Difluorophenyl)-7-(dimethyl- LC-MS (Method 1): R_(t) = 1.30min amino)-4-oxo-N-(1,1,1-trifluoropentan-2-yl)- MS (ESpos): m/z = 469.2[M + H]⁺ 1,4-dihydro-1,8-naphthyridine-3-carbox- ¹H-NMR (400 MHz,DMSO-d₆) δ [ppm]: amide −0.013 (4.68), 0.003 (4.35), 0.887 (7.06),

0.906 (16.00), 0.924 (8.19), 1.327 (1.40), 1.345 (1.67), 1.365 (1.60),1.384 (1.10), 1.436 (1.51), 1.620 (1.70), 1.647 (1.76), 1.765 (1.63),2.942 (6.60), 4.807 (1.43), 6.923 (9.13), 6.946 (9.28), 7.298 (1.43),7.320 (2.82), 7.341 (1.57), 7.544 (1.76), 7.551 (1.83), 7.570 (2.68),7.593 (1.82), 7.599 (1.70), 7.803 (2.27), 7.819 (2.25), 8.266 (10.01),8.289 (9.57), 8.608 (8.67), 10.482 (4.88), 10.505 (4.71). 145rac-1-(2,4-Difluorophenyl)-7-(dimethyl- LC-MS (Method 1): R_(t) = 1.35min amino)-4-oxo-N-(1,1,1-trifluoro-4- MS (ESpos): m/z = 483.3 [M + H]⁺methylpentan-2-yl)-1,4-dihydro-1,8-naph- ¹H-NMR (400 MHz, DMSO-d₆) δ[ppm]: thyridine-3-carboxamide −0.150 (1.26), −0.009 (16.00), 0.007(10.57),

0.146 (1.29), 0.880 (5.73), 0.895 (5.90), 0.941 (6.27), 0.957 (6.46),1.146 (0.73), 1.560 (1.57), 1.587 (1.17), 1.642 (1.65), 1.669 (2.24),1.696 (1.06), 2.072 (1.51), 2.322 (1.23), 2.327 (1.62), 2.331 (1.26),2.366 (1.23), 2.562 (0.81), 2.669 (1.73), 2.709 (1.45), 2.946 (3.80),4.829 (0.84), 6.928 (5.15), 6.950 (5.20), 7.301 (0.87), 7.318 (1.71),7.344 (0.98), 7.547 (1.01), 7.553 (1.01), 7.574 (1.54), 7.594 (0.90),7.602 (0.84), 7.792 (0.98), 7.813 (1.79), 7.828 (1.68), 7.850 (0.84),8.268 (5.62), 8.291 (5.29), 8.619 (7.16), 10.483 (2.69), 10.507 (2.69).146 rac-1-(2,4-Difluorophenyl)-7-(dimethyl- LC-MS (Method 1): R_(t) =1.24 min amino)-4-oxo-N-(1,1,1-trifluorobutan-2-yl)- MS (ESpos): m/z =455.2 [M + H]⁺ 1,4-dihydro-1,8-naphthyridine-3-carbox- ¹H-NMR (400 MHz,DMSO-d₆) δ [ppm]: amide −0.001 (4.33), 0.946 (7.55), 0.965 (16.00),

0.983 (7.69), 1.595 (1.19), 1.613 (1.56), 1.620 (1.42), 1.630 (1.86),1.638 (1.67), 1.648 (1.59), 1.655 (1.75), 1.673 (1.41), 1.848 (1.44),1.858 (1.61), 1.867 (1.61), 1.876 (1.78), 2.947 (7.03), 4.730 (1.52),6.929 (9.36), 6.951 (9.37), 7.304 (1.59), 7.321 (2.83), 7.347 (1.51),7.550 (1.86), 7.557 (1.92), 7.576 (2.68), 7.598 (1.83), 7.605 (1.69),7.804 (1.92), 8.275 (10.57), 8.297 (10.00), 8.614 (6.93), 10.490 (4.90),10.514 (4.63). 147 rac-1-(2,4-Difluorophenyl)-7-(dimethyl- LC-MS (Method1): R_(t) = 1.12 min amino)-4-oxo-N-(1,1,1-trifluoropropan-2-yl)- MS(ESpos): m/z = 441.2 [M + H]⁺ 1,4-dihydro-1,8-naphthyridine-3-carbox-¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: amide −0.150 (1.12), −0.020 (3.11),−0.018 (3.55),

−0.016 (4.21), −0.013 (5.41), −0.009 (14.12), 0.006 (5.28), 0.007(8.66), 0.012 (1.18), 0.145 (1.10), 1.360 (16.00), 1.377 (15.75), 2.520(2.59), 2.523 (2.85), 2.526 (2.97), 2.890 (1.83), 2.943 (6.81), 4.860(1.18), 4.880 (1.75), 4.901 (1.76), 4.919 (1.11), 6.927 (8.83), 6.949(8.89), 7.301 (1.35), 7.305 (1.53), 7.308 (1.40), 7.322 (2.65), 7.327(2.68), 7.344 (1.47), 7.348 (1.54), 7.351 (1.34), 7.551 (1.61), 7.558(1.67), 7.576 (2.49), 7.599 (1.58), 7.606 (1.51), 7.777 (1.17), 7.791(1.44), 7.799 (1.42), 7.808 (1.45), 7.823 (1.18), 8.267 (10.58), 8.290(9.97), 8.607 (6.25), 10.543 (3.19), 10.566 (3.05). 148rac-N-(1-Cyclopropyl-2,2,2-trifluoroethyl)- LC-MS (Method 1): R_(t) =1.19 min 1-(2,4-difluorophenyl)-7-(dimethylamino)-4- MS (ESpos): m/z =467.1 [M + H]⁺ oxo-1,4-dihydro-1,8-naphthyridine-3-carbox- ¹H-NMR (400MHz, DMSO-d₆) δ [ppm]: amide −0.009 (4.53), 0.007 (4.41), 0.327 (2.82),

0.497 (2.60), 0.509 (3.84), 0.521 (3.29), 0.531 (2.72), 0.542 (2.82),0.562 (3.54), 0.573 (3.26), 0.583 (2.87), 0.593 (2.39), 0.645 (2.81),0.657 (2.81), 0.667 (2.39), 1.182 (2.22), 1.194 (3.92), 1.203 (2.68),1.206 (2.53), 1.215 (3.80), 2.072 (3.10), 2.949 (9.68), 4.383 (3.15),4.405 (3.10), 6.930 (14.26), 6.953 (14.42), 7.302 (2.24), 7.305 (2.12),7.319 (4.12), 7.324 (4.25), 7.341 (2.27), 7.345 (2.40), 7.348 (2.24),7.548 (2.78), 7.555 (2.90), 7.574 (4.04), 7.578 (4.12), 7.580 (3.77),7.597 (2.92), 7.603 (2.87), 7.802 (3.38), 7.818 (3.35), 8.278 (16.00),8.301 (15.12), 8.603 (14.27), 10.622 (4.05), 10.644 (3.96). 1491-(2,4-Difluorophenyl)-7-(dimethylamino)- LC-MS (Method 1): R_(t) = 1.33min N-(1,1,1,3,3,3-hexafluoropropan-2-yl)-4-oxo- MS (ESpos): m/z = 495.2[M + H]⁺ 1,4-dihydro-1,8-naphthyridine-3-carbox- ¹H-NMR (400 MHz,DMSO-d₆) δ [ppm]: amide −0.009 (5.51), 0.007 (5.59), 2.322 (1.36),

2.327 (1.80), 2.332 (1.30), 2.366 (1.80), 2.669 (2.09), 2.710 (1.92),2.956 (4.44), 6.294 (1.45), 6.318 (1.56), 6.955 (8.61), 6.978 (8.77),7.312 (1.37), 7.334 (2.59), 7.355 (1.58), 7.558 (1.81), 7.565 (1.71),7.588 (2.61), 7.606 (1.75), 7.613 (1.76), 7.799 (1.84), 7.814 (2.03),7.820 (3.27), 7.835 (3.25), 7.842 (1.91), 7.857 (1.68), 8.293 (9.07),8.316 (8.62), 8.716 (16.00), 11.478 (4.79), 11.503 (4.49). 150rac-1-(2,4-Difluorophenyl)-7-(dimethyl- LC-MS (Method 1): R_(t) = 1.22min amino)-4-oxo-N-(1,1,1-trifluoro-3-methyl- MS (ESpos): m/z = 469.2[M + H]⁺ butan-2-yl)-1,4-dihydro-1,8-naphthyridine-3- ¹H-NMR (400 MHz,DMSO-d₆) δ [ppm]: carboxamide −0.150 (1.70), −0.009 (16.00), 0.007(14.74),

0.146 (1.81), 0.951 (8.74), 0.968 (8.97), 1.021 (7.68), 1.038 (7.74),2.245 (1.16), 2.949 (3.60), 4.769 (1.02), 6.929 (5.45), 6.952 (5.59),7.326 (1.56), 7.557 (1.03), 7.576 (1.53), 7.599 (1.02), 7.812 (1.31),7.828 (1.28), 8.300 (6.15), 8.323 (5.88), 8.622 (4.12), 10.677 (2.77),10.702 (2.67). 151 1-(2,4-Difluorophenyl)-7-(dimethylamino)-4- LC-MS(Method 1): R_(t) = 1.33 min oxo-N-[1-(trifluoromethyl)cyclopentyl]-1,4-MS (ESpos): m/z = 481.2 [M + H]⁺ dihydro-1,8-naphthyridine-3-carboxamide¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]:

−0.001 (16.00), 1.773 (0.24), 2.056 (0.17), 2.366 (0.17), 2.942 (0.38),6.920 (0.41), 6.942 (0.42), 7.325 (0.15), 7.578 (0.14), 7.791 (0.18),7.806 (0.18), 8.271 (0.46), 8.294 (0.44), 8.563 (0.84), 10.583 (0.47).152 N-(Bicyclo[2.2.2]oct-1-yl)-1-(2-chloro-4- LC-MS (Method 1): R_(t) =1.30 min fluorophenyl)-7-(dimethylamino)-4-oxo-1,4- MS (ESpos): m/z =469.1 [M + H]⁺ dihydro-1,8-naphthyridine-3-carboxamide ¹H-NMR (400 MHz,DMSO-d₆) δ [ppm]:

−0.013 (6.24), 0.003 (6.28), 1.540 (2.38), 1.547 (3.51), 1.555 (3.25),1.632 (9.41), 1.638 (9.20), 1.650 (8.75), 1.865 (10.16), 1.877 (8.30),1.887 (10.18), 1.905 (7.68), 2.885 (6.02), 2.900 (7.48), 6.867 (7.56),6.890 (7.82), 7.456 (3.08), 7.463 (3.36), 7.752 (3.65), 7.759 (6.96),7.773 (7.07), 7.781 (7.29), 7.795 (3.43), 8.239 (8.11), 8.261 (7.78),8.386 (16.00), 9.878 (7.48). 1531-(2-Chloro-4-fluorophenyl)-7-(dimethyl- LC-MS (Method 1): R_(t) = 1.39min amino)-4-oxo-N-[3-(trifluoromethyl)tricy- MS (ESpos): m/z = 563.1[M + H]⁺ clo[3.3.1.1^(3,7)]dec-1-yl]-1,4-dihydro-1,8-naph- ¹H-NMR (400MHz, DMSO-d₆) δ [ppm]: thyridine-3-carboxamide 1.639 (2.93), 1.671(4.03), 1.713 (10.59),

1.914 (3.34), 1.945 (4.32), 2.106 (4.81), 2.129 (13.92), 2.231 (5.97),2.908 (5.71), 6.886 (6.89), 6.909 (6.87), 7.457 (1.72), 7.471 (3.06),7.478 (3.24), 7.500 (2.00), 7.773 (5.39), 7.796 (5.10), 7.810 (3.24),8.249 (7.62), 8.271 (7.26), 8.411 (16.00), 10.124 (7.70). 1541-(2-Chloro-4-fluorophenyl)-7-(dimethyl- LC-MS (Method 1): R_(t) = 1.36min amino)-4-oxo-N-(spiro[2.5]oct-1-yl)-1,4-dihy- MS (ESpos): m/z =469.2 [M + H]⁺ dro-1,8-naphthyridine-3-carboxamide ¹H-NMR (400 MHz,DMSO-d₆) δ [ppm]:

−0.009 (5.56), 0.007 (3.50), 0.337 (1.60), 0.350 (3.09), 0.362 (2.78),0.375 (1.28), 0.725 (1.89), 0.739 (2.80), 0.757 (1.66), 1.269 (1.62),1.328 (1.59), 1.440 (3.49), 1.470 (6.97), 2.669 (0.55), 2.721 (1.33)2.732 (2.29), 2.751 (2.17), 2.763 (1.19), 2.909 (6.10), 6.877 (7.56),6.900 (7.61), 7.445 (1.59), 7.453 (1.80), 7.467 (2.80), 7.474 (2.89),7.488 (1.78), 7.495 (1.91), 7.764 (3.55), 7.771 (5.42), 7.786 (6.06),7.793 (5.35), 7.802 (1.98), 7.807 (2.24), 7.824 (1.44), 8.254 (8.13),8.277 (7.61), 8.437 (0.53), 8.468 (16.00), 10.048 (2.79), 10.062 (2.29).155 N-tert-Butyl-1-(2-chloro-4-fluorophenyl)-7- LC-MS (Method 1): R_(t)= 1.22 min (dimethylamino)-4-oxo-1,4-dihydro-1,8- MS (ESpos): m/z =417.2 [M + H]⁺ naphthyridine-3-carboxamide ¹H-NMR (400 MHz, DMSO-d₆) δ[ppm]:

−0.009 (1.09), 0.007 (1.06), 1.387 (16.00), 1.405 (0.38), 2.522 (0.31),2.908 (1.02), 6.880 (1.21), 6.903 (1.22), 7.445 (0.26), 7.452 (0.29),7.466 (0.45), 7.473 (0.49), 7.487 (0.30), 7.494 (0.34), 7.763 (0.54),7.769 (1.06), 7.784 (1.13), 7.791 (1.06), 7.805 (0.53), 8.253 (1.27),8.275 (1.20), 8.423 (2.46), 10.033 (1.08). 1561-(2-Chloro-4-fluorophenyl)-7-(dimethyl- LC-MS (Method 1): R_(t) = 1.28min amino)-N-(1-methylcyclohexyl)-4-oxo-1,4-di- MS (ESpos): m/z = 457.1[M + H]⁺ hydro-1,8-naphthyridine-3-carboxamide ¹H-NMR (400 MHz, DMSO-d₆)δ [ppm]:

−0.150 (0.51), −0.009 (4.50), 0.007 (3.96), 0.146 (0.48), 1.225 (0.49),1.240 (0.53), 1.343 (1.13), 1.382 (16.00), 1.459 (0.75), 1.495 (2.35),1.505 (2.20), 1.558 (0.57), 2.072 (0.55), 2.105 (0.98), 2.322 (0.45),2.327 (0.59), 2.331 (0.44), 2.366 (0.57), 2.523 (1.30), 2.664 (0.52),2.669 (0.68), 2.674 (0.50), 2.709 (0.65), 2.911 (2.70), 6.882 (3.55),6.905 (3.65), 7.444 (0.76), 7.451 (0.90), 7.465 (1.31), 7.472 (1.48),7.486 (0.91), 7.493 (1.02), 7.762 (1.52), 7.769 (1.68), 7.776 (1.81),7.784 (1.75), 7.791 (3.15), 7.798 (1.70), 7.812 (1.59), 8.276 (3.96),8.299 (3.71), 8.419 (8.02), 10.045 (2.98). 1571-(2-Chloro-4-fluorophenyl)-7-(dimethyl- LC-MS (Method 1): R_(t) = 1.59min amino)-N-(3-ethyltricyclo[3.3.1.1^(3,7)]dec-1-yl)- MS (ESpos): m/z =523.3 [M + H]⁺ 4-oxo-1,4-dihydro-1,8-naphthyridine-3-car- ¹H-NMR (400MHz, DMSO-d₆) δ [ppm]: boxamide −0.150 (1.83), −0.009 (16.00), 0.007(14.17),

0.146 (1.83), 0.766 (3.31), 0.785 (8.94), 0.803 (4.23), 1.125 (1.12),1.144 (3.75), 1.163 (3.04), 1.182 (0.90), 1.403 (6.87), 1.528 (0.66),1.560 (1.24), 1.613 (1.23), 1.644 (0.71), 1.742 (5.91), 1.959 (2.01),2.016 (2.78), 2.044 (1.35), 2.108 (2.98), 2.322 (1.08), 2.326 (1.39),2.331 (1.04), 2.365 (1.34), 2.664 (1.16), 2.669 (1.54), 2.674 (1.12),2.709 (1.39), 2.904 (3.63), 6.878 (4.36), 6.901 (4.54), 7.446 (0.93),7.453 (1.12), 7.467 (1.66), 7.475 (1.90), 7.488 (1.08), 7.495 (1.29),7.764 (2.14), 7.771 (4.16), 7.785 (4.35), 7.792 (4.13), 7.806 (1.99),8.248 (5.12), 8.270 (4.82), 8.392 (10.95), 9.982 (4.20).

Example 1581-(2,4-Difluorophenyl)-4-oxo-7-(propan-2-ylamino)-N-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

To 100 mg (0.28 mmol) of the compound from Example 38A and 70 mg (0.7mmol) of N-methylmorpholine in 2.5 ml of DMF was added, at 0° C., 0.56ml (0.56 mmol) of isopropyl chloroformate (1 M in toluene), and themixture was stirred at 0° C. for 1 h. Then, at 0° C., 34 mg (0.22 mmol)of 1-adamantanamine were added and the mixture was stirred at 20° C. for2 hours. After 12 h, the mixture was purified via preparative HPLC(eluent: acetonitrile/water gradient with 0.1% formic acid). This gave 2mg (2% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.39 min; m/z=493.3 [M+H]⁺.

¹H-NMR (400 MHz, CDCl₃) δ [ppm]: 1.098 (4.13), 1.117 (4.71), 1.132(3.93), 1.265 (2.61), 1.567 (12.87), 1.691 (1.63), 1.721 (5.40), 1.745(5.60), 1.775 (1.65), 2.015 (1.00), 2.117 (5.05), 2.185 (16.00), 3.500(0.95), 3.693 (0.81), 3.710 (1.29), 3.727 (1.30), 3.743 (0.82), 4.797(1.15), 4.814 (1.12), 6.410 (2.16), 6.432 (2.22), 6.997 (1.04), 7.015(2.62), 7.036 (2.60), 7.052 (1.03), 7.336 (0.81), 7.357 (1.29), 7.371(1.35), 7.393 (0.61), 8.344 (2.01), 8.365 (1.98), 8.624 (6.01), 9.938(2.22).

In analogy to Example 158, the example compound shown in Table 17 wasprepared, by reacting the compound from Example 38A with the appropriateamines (or salts thereof) under the reaction conditions described.Differences are specified in the respective examples.

TABLE 17 Ex. Analytical data 159

LC-MS (Method 1): R_(t) = 1.27 min MS (ESpos): m/z = 467.2 [M + H]⁺¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.019 (1.74), −0.016 (2.07), −0.009(6.78), 0.005 (3.03), 0.007 (4.37), 0.949 (9.89), 0.963 (11.01), 0.995(13.19), 1.011 (11.80), 1.542 (3.78), 1.549 (5.44), 1.557 (4.95), 1.583(1.41), 1.633 (15.56), 1.639 (15.24), 1.651 (14.55), 1.818 (3.29), 1.839(3.03), 1.867 (16.00), 1.878 (13.44), 1.888 (15.97), 1.906 (11.40),2.072 (2.38), 2.523 (3.78), 2.526 (4.13), 3.497 (1.95), 3.513 (1.94),6.586 (5.23), 6.608 (5.28), 7.278 (2.03), 7.282 (2.25), 7.285 (2.19),7.299 (3.89), 7.303 (4.11), 7.321 (2.28), 7.325 (2.35), 7.328 (2.17),7.336 (2.29), 7.356 (2.15), 7.524 (2.49), 7.531 (2.79), 7.550 (3.94),7.554 (4.11), 7.572 (2.66), 7.579 (2.48), 7.742 (4.31), 7.757 (3.59),7.764 (5.12), 7.779 (4.76), 7.786 (2.93), 7.801 (2.21), 8.098 (4.22),8.120 (4.08), 8.427 (15.57), 8.447 (2.59), 9.912 (9.63), 10.202 (1.52).

Example 1601-(2,4-Difluorophenyl)-7-(methylamino)-4-oxo-N-[3-(trifluoromethyl)tricyclo[3.3.1.1^(3,7)]dec-1-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

To 80 mg (0.24 mmol) of the compound from Example 37A and 61 mg (0.6mmol) of N-methylmorpholine in 2.2 ml of DMF was added, at 0° C., 0.48ml (0.48 mmol) of isopropyl chloroformate (1 M in toluene), and themixture was stirred at 0° C. for 1 h. Then, at 0° C., 34 mg (0.22 mmol)of 1-(3-trifluoromethyl)adamantanamine were added and the mixture wasstirred at 20° C. for 2 hours. After 12 h, the mixture was purified viapreparative HPLC (eluent: acetonitrile/water gradient with 0.1% formicacid). This gave 57 mg (42% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.27 min; m/z=533.1 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.009 (6.50), 0.007 (6.34), 1.639(3.23), 1.668 (4.16), 1.714 (11.64), 1.915 (4.17), 1.942 (5.42), 2.107(6.21), 2.128 (16.00), 2.230 (6.76), 3.672 (1.64), 5.753 (4.27), 6.622(5.65), 6.645 (5.71), 7.295 (1.67), 7.317 (3.10), 7.338 (1.74), 7.538(2.09), 7.544 (2.19), 7.567 (3.02), 7.586 (2.14), 7.593 (2.09), 7.756(2.14), 7.778 (4.13), 7.793 (4.26), 7.815 (2.78), 8.141 (1.63), 8.447(11.87), 10.142 (6.07).

In analogy to Example 160, the example compounds shown in Table 18 wereprepared by reacting the compound from Example 37A with the appropriateamines (or salts thereof) under the reaction conditions described.Differences are specified in the respective examples.

TABLE 18 Ex. Analytical data 161

LC-MS (Method 1): R_(t) = 1.16 min MS (ESpos): m/z = 501.3 [M + H]⁺¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.005 (16.00), 1.740 (1.03), 1.783(7.48), 1.820 (1.02), 2.061 (12.90), 2.272 (6.60), 2.297 (4.96), 6.615(3.10), 6.637 (3.14), 7.287 (1.11), 7.309 (2.02), 7.329 (1.05), 7.530(1.11), 7.537 (1.20), 7.559 (1.89), 7.578 (1.13), 7.585 (1.13), 7.754(1.14), 7.769 (1.46), 7.775 (2.28), 7.790 (2.33), 7.797 (1.64), 7.812(1.67), 8.116 (1.04), 8.136 (1.04), 8.442 (5.93), 10.085 (3.75). 162

LC-MS (Method 1): R_(t) = 1.17 min MS (ESpos): m/z = 439.1 [M + H]⁺¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 1.546 (5.04), 1.631 (14.89), 1.863(15.35), 1.885 (16.00), 1.903 (11.48), 2.068 (2.97), 6.605 (5.86), 6.627(5.97), 7.304 (3.93), 7.531 (2.28), 7.555 (3.73), 7.573 (2.19), 7.768(4.61), 7.783 (4.99), 7.805 (3.68), 8.111 (2.11), 8.423 (11.13), 9.900(7.11).

Example 163N-(2,6-Dichlorophenyl)-1-(2,4-difluorophenyl)-4-oxo-7-[(2,2,2-trifluoroethyl)amino]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

152 mg (0.94 mmol) of 2,6-dichloroaniline were dissolved in 10 ml ofdichloromethane, 0.94 ml (0.94 mmol) of trimethylaluminium (1 M solutionin toluene) was added and the mixture was stirred at 23° C. (underargon) for one hour. Then 200 mg (0.47 mmol) of the compound fromExample 30A were added and the mixture was stirred at 23° C. for 16 h. 5ml of water were added, then the mixture was filtered through kieselguhrand washed with ethyl acetate and methanol, and the combined eluateswere concentrated under reduced pressure. The residue was purified bypreparative HPLC (Method 7). This gave 57 mg (22% of theory) of thetitle compound.

LC-MS (Method 1): R_(t)=1.11 min; m/z=543.1 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.031 (2.20), −0.020 (3.38), −0.017(3.92), −0.009 (13.57), 0.005 (4.57), 0.007 (7.84), 1.156 (3.89), 1.174(7.63), 1.192 (3.94), 1.249 (2.03), 1.987 (12.97), 2.520 (4.06), 2.523(4.45), 3.863 (1.67), 3.885 (1.55), 4.020 (3.06), 4.037 (2.99), 6.844(2.50), 6.866 (2.42), 7.324 (2.25), 7.330 (2.28), 7.355 (4.12), 7.375(5.28), 7.396 (4.49), 7.540 (1.76), 7.547 (1.79), 7.577 (16.00), 7.589(2.18), 7.597 (12.49), 7.815 (1.39), 7.830 (1.72), 7.837 (2.62), 7.852(2.82), 7.859 (1.49), 8.359 (5.18), 8.381 (4.91), 8.500 (1.33), 8.730(11.18), 11.946 (7.80).

Example 164 Methyl4-{6-[(2,6-dichlorophenyl)carbamoyl]-8-(2,4-difluorophenyl)-5-oxo-5,8-dihydro-1,8-naphthyridin-2-yl}piperazine-1-carboxylate

77 mg (0.47 mmol) of 2,6-dichloroaniline were dissolved indichloromethane, 0.47 ml (0.47 mmol) of trimethylaluminium (1 M solutionin toluene) was added and the mixture was stirred at 23° C. (underargon) for one hour. Then 120 mg (0.24 mmol) of the compound fromExample 29A were added and the mixture was stirred at 23° C. for 16 h.The mixture was purified by preparative HPLC (Method 7). This gave 80 mg(57% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.10 min; m/z=588.1 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.009 (2.56), 0.007 (2.34), 1.156(2.57), 1.174 (5.27), 1.192 (2.63), 1.987 (9.53), 2.522 (1.04), 2.524(0.92), 3.394 (3.43), 3.407 (2.81), 3.536 (3.09), 3.610 (16.00), 4.002(0.76), 4.020 (2.20), 4.038 (2.22), 4.055 (0.75), 7.132 (2.23), 7.155(2.27), 7.336 (0.99), 7.354 (1.74), 7.375 (2.28), 7.395 (1.92), 7.576(6.94), 7.597 (6.13), 7.840 (1.12), 7.855 (1.12), 8.381 (3.02), 8.403(2.84), 8.713 (6.16), 11.950 (3.67).

Example 1651-(2,4-Difluorophenyl)-4-oxo-7-(2-oxopiperidin-1-yl)-N-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

104 mg (0.32 mmol) of caesium carbonate, 5 mg (0.02 mmol) ofpalladium(II) acetate and 12 mg (0.02 mmol) of Xantphos were stirred in5 ml of dioxane under argon at 20° C. for 10 minutes. Then 100 mg (0.21mmol) of the compound from Example 65A and 25 mg (0.26 mmol) of6-valerolactam were added and the mixture was stirred at 80° C. for 1 h.Subsequently, the mixture was added to 30 ml of water and brought to pH1 with 1 M aqueous hydrochloric acid. The precipitated solid wasfiltered off with suction and washed with water, petroleum ether andacetonitrile. The residue was then dissolved in DCM, activated carbonwas added and then the mixture was stirred at RT. The mixture wasfiltered through kieselguhr and the volatile constituents were thenremoved under reduced pressure. The residue was purified via preparativethin-layer chromatography (eluent: THF; extractant: ethyl acetate). Theproduct-containing fractions were concentrated under reduced pressureand the residue was then stirred with 1 M aqueous hydrochloric acid. Theprecipitate was then filtered off, washed with water, acetonitrile andethyl acetate and dried under high vacuum. This gave 12 mg (10% oftheory) of the title compound.

LC-MS (Method 1): R_(t)=1.35 min; m/z=533.5 [M+H]⁺.

¹H-NMR (400 MHz, CDCl₃) δ [ppm]: 1.265 (0.20), 1.442 (0.16), 1.567(16.00), 1.730 (0.51), 1.750 (0.51), 1.852 (0.42), 2.129 (0.45), 2.187(1.47), 3.597 (0.23), 7.040 (0.12), 7.060 (0.35), 7.079 (0.32), 7.394(0.12), 7.409 (0.12), 8.176 (0.45), 8.198 (0.48), 8.672 (0.49), 8.694(0.44), 8.807 (0.77), 9.701 (0.22).

Example 1661-(2,4-Difluorophenyl)-4-oxo-7-(2-oxopyrrolidin-1-yl)-N-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

208 mg (0.64 mmol) of caesium carbonate, 10 mg (0.04 mmol) ofpalladium(II) acetate and 25 mg (0.04 mmol) of Xantphos were stirred in5.6 ml of dioxane (under argon) at 20° C. for 10 minutes. Then 200 mg(0.43 mmol) of the compound from Example 65A and 36 mg (0.43 mmol) of2-pyrrolidinone were added and the mixture was stirred at 110° C. for 22h. Subsequently, the mixture was filtered and the filtrate was purifiedvia preparative HPLC (eluent: acetonitrile/water gradient with 0.1%formic acid). This gave 13 mg (6% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.33 min; m/z=519.2 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.150 (1.78), −0.009 (16.00), 0.008(15.04), 0.146 (1.89), 1.146 (0.80), 1.235 (0.55), 1.679 (4.33), 1.956(0.66), 1.976 (0.50), 2.072 (9.96), 2.322 (1.13), 2.327 (1.68), 2.331(1.16), 2.365 (1.94), 2.523 (4.23), 2.525 (3.79), 2.558 (2.30), 2.575(1.51), 2.582 (1.43), 2.595 (0.88), 2.665 (1.49), 2.669 (1.89), 2.674(1.46), 2.709 (2.20), 3.286 (1.67), 3.426 (0.36), 3.549 (0.83), 3.570(0.83), 3.587 (0.49), 7.354 (0.52), 7.616 (0.53), 7.642 (0.36), 7.845(0.57), 7.860 (0.58), 8.464 (1.62), 8.486 (1.97), 8.658 (1.94), 8.680(1.65), 8.705 (2.97), 9.725 (1.56).

In analogy to Example 166, the example compounds shown in Table 19 wereprepared by reacting the compound from Example 65A with the appropriateamines (or salts thereof) under the reaction conditions described.Differences are specified in the respective examples.

TABLE 19 Ex. Analytical data 167

LC-MS (Method 1): R_(t) = 1.26 min MS (ESpos): m/z = 555.2 [M + H]⁺¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.013 (1.19), 0.003 (1.16), 1.672(7.13), 2.063 (16.00), 2.067 (13.86), 2.091 (0.91), 2.297 (1.24), 2.315(1.97), 2.332 (1.36), 3.575 (0.95), 3.594 (2.09), 3.606 (2.00), 3.616(1.55), 3.634 (0.64), 7.320 (0.73), 7.325 (0.76), 7.340 (2.97), 7.362(2.60), 7.537 (0.49), 7.555 (0.69), 7.559 (0.70), 7.578 (0.50), 7.813(0.54), 7.820 (0.91), 7.835 (0.91), 7.842 (0.52), 8.612 (2.64), 8.634(2.52), 8.653 (4.54), 9.730 (2.56). 168

LC-MS (Method 1): R_(t) = 1.31 min MS (ESpos): m/z = 505.4 [M + H]⁺¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 1.156 (0.38), 1.174 (0.71), 1.192(0.39), 1.234 (0.73), 1.676 (7.37), 1.987 (1.27), 2.067 (16.00), 2.327(0.39), 2.365 (0.42), 2.669 (0.41), 2.709 (0.40), 3.088 (1.46), 3.100(1.49), 3.386 (1.28), 4.020 (0.29), 4.038 (0.29), 7.327 (0.44), 7.349(0.82), 7.366 (0.61), 7.576 (0.50), 7.598 (0.77), 7.618 (0.50), 7.696(2.27), 7.717 (2.38), 7.810 (0.46), 7.832 (0.88), 7.847 (0.90), 7.869(0.46), 8.654 (2.35), 8.675 (2.58), 8.681 (4.17), 9.709 (2.41). 169

LC-MS (Method 1): R_(t) = 1.26 min MS (ESpos): m/z = 543.2 [M + H]⁺¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.154 (0.08), −0.005 (16.00), 0.141(0.08), 1.674 (2.57), 2.068 (8.74), 3.036 (4.34), 3.226 (4.18), 7.329(0.13), 7.351 (0.27), 7.372 (0.14), 7.540 (0.80), 7.562 (0.83), 7.576(0.17), 7.594 (0.25), 7.617 (0.17), 7.624 (0.16), 7.823 (0.15), 7.845(0.31), 7.860 (0.31), 7.867 (0.18), 7.881 (0.15), 8.630 (0.81), 8.653(0.77), 8.699 (1.49), 9.689 (0.87). 170

LC-MS (Method 1): R_(t) = 1.16 min MS (ESpos): m/z = 535.2 [M + H]⁺¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.149 (1.21), −0.008 (10.86), 0.008(9.92), 0.146 (1.23), 1.147 (0.47), 1.676 (8.65), 2.059 (8.89), 2.072(16.00), 2.327 (1.28), 2.366 (1.28), 2.391 (0.39), 2.524 (2.59), 2.670(1.06), 2.674 (0.83), 2.710 (1.13), 2.899 (0.30), 2.932 (0.38), 3.288(1.29), 3.441 (0.36), 3.466 (0.65), 3.499 (0.39), 3.637 (0.32), 3.667(0.50), 4.284 (0.71), 5.283 (0.52), 5.343 (0.51), 7.368 (0.63), 7.601(0.62), 7.621 (0.76), 7.649 (0.38), 7.845 (0.52), 7.864 (0.57), 8.365(0.43), 8.467 (0.57), 8.481 (0.65), 8.503 (0.80), 8.666 (2.59), 8.688(2.08), 8.704 (4.17), 9.725 (2.21). 171

LC-MS (Method 1): R_(t) = 1.31 min MS (ESpos): m/z = 569.3 [M + H]⁺¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 1.680 (7.72), 2.075 (16.00), 2.366(1.00), 2.387 (0.85), 2.406 (1.26), 2.424 (0.94), 2.444 (0.66), 2.720(1.48), 2.738 (2.68), 2.756 (1.18), 3.955 (1.20), 3.987 (2.25), 4.019(1.16), 7.388 (0.84), 7.641 (0.46), 7.661 (0.78), 7.683 (0.45), 7.857(0.42), 7.878 (0.82), 7.894 (0.81), 7.915 (0.40), 8.155 (1.85), 8.177(2.01), 8.670 (2.00), 8.692 (1.84), 8.749 (3.57), 9.679 (2.44). 172

LC-MS (Method 1): R_(t) = 1.28 min MS (ESpos): m/z = 535.2 [M + H]⁺¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.150 (1.50), −0.009 (13.61), 0.007(12.45), 0.146 (1.55), 1.146 (0.70), 1.590 (0.77), 1.681 (7.53), 2.075(16.00), 2.322 (1.13), 2.327 (1.57), 2.331 (1.05), 2.366 (1.89), 2.522(3.55), 2.665 (1.16), 2.669 (1.59), 2.673 (1.17), 2.709 (1.95), 3.544(1.38), 3.558 (2.29), 3.570 (1.65), 3.898 (1.63), 4.277 (3.49), 4.284(3.49), 7.355 (0.77), 7.605 (0.85), 7.861 (0.97), 7.876 (0.88), 8.339(2.75), 8.361 (3.02), 8.681 (3.13), 8.703 (2.70), 8.739 (4.78), 9.687(2.58). 173

LC-MS (Method 1): R_(t) = 1.12 min MS (ESpos): m/z = 549.3 [M + H]⁺¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.150 (1.72), −0.009 (14.59), 0.007(14.85), 0.083 (0.31), 0.146 (1.85), 1.146 (0.73), 1.156 (0.94), 1.174(1.95), 1.192 (0.90), 1.237 (0.44), 1.672 (7.27), 1.987 (3.59), 2.059(16.00), 2.322 (1.28), 2.327 (1.93), 2.365 (2.81), 2.523 (5.04), 2.669(2.18), 2.673 (1.72), 2.709 (2.92), 3.432 (0.48), 3.682 (0.31), 4.020(1.01), 4.037 (0.80), 4.056 (0.34), 6.840 (0.42), 7.319 (0.42), 7.337(0.82), 7.360 (0.57), 7.575 (0.55), 7.606 (0.86), 7.631 (0.52), 7.821(0.76), 7.837 (0.59), 8.470 (0.46), 8.519 (1.15), 9.805 (0.84), 12.106(1.28).

Example 1741-(2,4-Difluorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-yl]-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

412 mg (1.3 mmol) of caesium carbonate, 34 mg (0.15 mmol) ofpalladium(II) acetate and 88 mg (0.15 mmol) of Xantphos were stirred indioxane (under an argon atmosphere) at 20° C. for 10 minutes. Then 400mg (0.84 mmol) of the compound from Example 68A and 85 mg (0.84 mmol) of(4S)-4-hydroxy-pyrrolidin-2-one were added and the mixture was stirredat 80° C. for 40 min. Subsequently, the mixture was added to water andbrought to pH 1 with 1 M aqueous hydrochloric acid. The precipitatedsolid was filtered off with suction, washed with water and petroleumether, and then purified by column chromatography (silica gel cartridge;cyclohexane/ethyl acetate gradient (5:1-2:1-1:1). This gave 169 mg (38%of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.01 min; m/z=511.3 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.001 (16.00), 0.958 (1.16), 0.976(2.31), 0.995 (1.20), 1.174 (0.23), 1.234 (0.33), 1.565 (0.20), 1.686(0.37), 1.894 (0.30), 1.987 (0.32), 2.336 (0.30), 2.379 (0.33), 2.943(0.26), 3.437 (0.27), 3.469 (0.43), 3.503 (0.26), 3.674 (0.30), 4.288(0.45), 4.764 (0.26), 5.293 (0.38), 5.343 (0.30), 7.373 (0.37), 7.629(0.42), 7.877 (0.31), 8.516 (0.39), 8.538 (0.45), 8.698 (1.21), 8.720(1.05), 8.849 (0.86), 10.208 (0.55), 10.232 (0.57).

In analogy to Example 174, the example compounds shown in Table 20 wereprepared by reacting the respective compounds from Examples 66A-70A withthe appropriate amines (or salts thereof) under the reaction conditionsdescribed. Differences are specified in the respective examples.

TABLE 20 Ex. Analytical data 175

LC-MS (Method 1): R_(t) = 0.99 min; m/z = 511.4 [M + H]⁺. ¹H-NMR (500MHz, DMSO-d₆) δ [ppm]: −0.009 (0.77), −0.003 (16.00), 0.004 (0.49),0.964 (5.50), 0.979 (11.59), 0.994 (5.60), 1.634 (0.80), 1.640 (0.40),1.649 (1.07), 1.654 (0.94), 1.662 (1.26), 1.669 (1.12), 1.677 (1.07),1.683 (1.16), 1.697 (0.87), 1.865 (0.40), 1.872 (0.89), 1.879 (1.04),1.886 (1.06), 1.894 (1.17), 1.899 (1.06), 1.908 (0.94), 1.914 (0.79),1.922 (0.66), 2.342 (1.02), 2.362 (1.10), 2.376 (1.18), 2.397 (1.08),2.898 (0.72), 2.910 (0.78), 2.933 (1.41), 2.945 (1.40), 2.967 (0.70),2.979 (0.64), 3.444 (0.98), 3.468 (1.29), 3.479 (1.06), 3.503 (1.12),3.632 (0.76), 3.642 (0.89), 3.656 (0.78), 3.667 (1.25), 3.677 (0.91),3.692 (0.70), 3.701 (0.60), 4.286 (2.23), 4.759 (0.98), 4.765 (1.02),4.778 (0.96), 4.793 (0.54), 5.294 (0.49), 5.348 (0.44), 5.752 (2.39),7.354 (0.90), 7.371 (1.72), 7.388 (0.93), 7.608 (1.00), 7.627 (1.78),7.646 (0.98), 7.869 (1.43), 7.880 (1.22), 7.886 (1.37), 8.503 (1.49),8.520 (2.77), 8.537 (1.79), 8.700 (8.73), 8.718 (7.10), 8.850 (3.69),8.857 (3.69), 10.211 (3.77), 10.230 (3.59). 176

LC-MS (Method 1): R_(t) = 1.01 min; m/z = 511.1 [M + H]⁺. ¹H-NMR (400MHz, DMSO-d₆) δ [ppm]: −0.009 (6.49), 0.007 (6.13), 0.898 (1.89), 0.960(7.36), 0.978 (15.05), 0.996 (7.39), 1.156 (3.78), 1.174 (7.50), 1.192(3.75), 1.625 (1.27), 1.643 (1.78), 1.650 (1.47), 1.660 (1.95), 1.669(1.81), 1.679 (1.62), 1.686 (1.92), 1.704 (1.44), 1.866 (1.43), 1.876(1.62), 1.885 (1.74), 1.894 (1.69), 1.901 (1.72), 1.908 (1.51), 1.987(14.10), 2.335 (1.77), 2.357 (1.34), 2.378 (1.74), 2.400 (1.55), 2.906(1.12), 2.942 (1.40), 3.439 (1.38), 3.470 (2.50), 3.503 (1.70), 3.640(1.26), 3.664 (1.63), 4.020 (3.12), 4.038 (3.14), 4.280 (2.69), 4.764(1.63), 4.778 (1.57), 5.287 (2.24), 5.295 (2.18), 5.344 (1.88), 5.354(1.85), 5.753 (16.00), 7.373 (2.43), 7.607 (1.71), 7.630 (2.72), 7.653(1.31), 7.870 (1.88), 8.502 (2.22), 8.516 (2.66), 8.524 (2.78), 8.539(2.90), 8.699 (12.77), 8.721 (10.04), 8.849 (5.98), 8.855 (5.41), 10.209(4.47), 10.233 (4.26). 177

LC-MS (Method 1): R_(t) = 1.15 min; m/z = 495.3 [M + H]⁺. ¹H-NMR (400MHz, DMSO-d₆) δ [ppm]: −0.150 (1.83), −0.009 (16.00), 0.007 (15.91),0.146 (1.93), 0.958 (5.12), 0.977 (11.28), 0.995 (5.59), 1.156 (2.03),1.174 (3.85), 1.192 (2.09), 1.234 (2.67), 1.642 (1.04), 1.659 (1.22),1.685 (1.20), 1.703 (0.89), 1.894 (1.21), 1.947 (2.11), 1.962 (2.97),1.987 (5.90), 2.327 (1.10), 2.366 (1.85), 2.563 (3.59), 2.582 (4.46),2.590 (4.72), 2.602 (2.58), 2.610 (2.36), 2.669 (1.47), 2.709 (2.18),3.533 (1.53), 3.550 (2.74), 3.573 (2.86), 3.591 (1.58), 4.020 (1.08),4.038 (1.03), 4.764 (1.01), 7.339 (0.95), 7.360 (1.97), 7.381 (1.09),7.598 (1.26), 7.620 (1.88), 7.639 (1.26), 7.646 (1.22), 7.878 (1.35),8.500 (6.13), 8.522 (7.62), 8.690 (7.51), 8.713 (6.15), 8.850 (3.94),10.209 (3.35), 10.232 (3.25). 178

LC-MS (Method 1): R_(t) = 1.15 min; m/z = 509.4 [M + H]⁺. ¹H-NMR (400MHz, DMSO-d₆) δ [ppm]: 0.959 (8.20), 0.978 (16.00), 0.996 (7.69), 1.662(2.25), 1.755 (15.41), 1.894 (1.98), 3.526 (7.02), 4.765 (1.79), 7.342(1.95), 7.363 (3.27), 7.602 (2.15), 7.624 (3.24), 7.643 (1.92), 7.869(2.39), 8.133 (8.33), 8.155 (8.74), 8.624 (8.95), 8.646 (8.06), 8.860(6.39), 10.191 (4.92), 10.214 (4.57). 179

LC-MS (Method 1): R_(t) = 1.12 min; m/z = 481.2 [M + H]⁺. ¹H-NMR (400MHz, DMSO-d₆) δ [ppm]: −0.150 (1.18), −0.009 (10.63), 0.007 (10.36),0.145 (1.32), 1.381 (15.86), 1.399 (16.00), 1.946 (2.60), 1.960 (3.95),1.981 (3.04), 2.365 (1.72), 2.561 (4.22), 2.580 (5.74), 2.588 (6.01),2.601 (3.24), 2.608 (2.87), 2.669 (1.28), 2.709 (1.89), 3.531 (2.16),3.549 (3.95), 3.570 (3.71), 4.912 (1.69), 4.933 (1.69), 7.339 (1.49),7.361 (2.84), 7.382 (1.99), 7.598 (1.65), 7.620 (2.46), 7.639 (1.69),7.855 (1.59), 8.496 (8.78), 8.518 (10.67), 8.681 (11.27), 8.703 (9.08),8.843 (5.97), 10.258 (3.24), 10.281 (3.07). 180

LC-MS (Method 1): R_(t) = 1.09 min; m/z = 531.1 [M + H]⁺. ¹H-NMR (400MHz, DMSO-d₆) δ [ppm]: −0.009 (4.11), 0.007 (2.26), 0.957 (7.72), 0.975(16.00), 0.993 (7.78), 1.620 (1.16), 1.638 (1.63), 1.646 (1.74), 1.655(1.95), 1.663 (1.71), 1.673 (1.65), 1.680 (1.79), 1.698 (1.35), 1.862(1.46), 1.872 (1.66), 1.881 (1.67), 1.890 (1.83), 1.897 (1.61), 1.907(1.46), 1.915 (1.14), 1.925 (0.98), 1.987 (1.19), 2.290 (1.50), 2.307(5.22), 2.325 (8.04), 2.342 (5.26), 2.359 (1.49), 3.593 (4.45), 3.603(8.33), 3.610 (8.78), 3.619 (8.50), 3.629 (6.96), 3.647 (2.73), 4.757(1.58), 4.774 (1.48), 7.310 (1.63), 7.326 (2.99), 7.331 (3.06), 7.347(1.80), 7.352 (1.81), 7.374 (8.75), 7.396 (8.90), 7.537 (1.80), 7.543(1.86), 7.562 (2.84), 7.566 (2.80), 7.585 (1.80), 7.592 (1.66), 7.818(1.14), 7.838 (2.25), 7.854 (2.25), 7.875 (1.01), 8.647 (8.78), 8.669(8.39), 8.804 (8.06), 10.221 (5.01), 10.245 (4.79). 181

LC-MS (Method 1): R_(t) = 1.15 min; m/z = 523.4 [M + H]⁺. ¹H-NMR (400MHz, DMSO-d₆) δ [ppm]: 0.8 (s, 3H), 1.43-1.52 (m, 6H), 1.89-1.98 (m,6H), 3.41-3.52 (m, 1H), 3.59-3.72 (m, 1H), 4.24-4.30 (m, 2H), 5.26-5.30(m, 0.5H), 5.32-5.35 (m, 0.5H), 7.32-7.40 (m, 1H), 7.54-7.66 (m, 1H),7.77-7.90 (m, 1H), 8.45- 8.51 (m, 1H), 8.67 (d, 1H), 8.70 (s, 1H), 9.66(s, 1H).

Example 182N-(2,6-Dichlorobenzyl)-1-(2,4-difluorophenyl)-7-(1,1-dioxido-1,2-thiazolidin-2-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide

7 mg (0.03 mmol) of palladium(II) acetate and 18 mg (0.03 mmol) ofXantphos were stirred in 3.6 ml of dioxane under an argon atmosphere at20° C. for 10 minutes. Then 150 mg (0.3 mmol) of the compound fromExample 72A, 74 mg (0.06 mmol) of 1,3-propane sultam and 148 mg (0.46mmol) of caesium carbonate were added and the mixture was stirred at110° C. for 6 h. After cooling down to 23° C., the mixture was purifiedvia preparative HPLC (eluent: acetonitrile/water gradient with 0.1%formic acid). This gave 95 mg (51% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.15 min; m/z=579.2 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 1.156 (4.54), 1.174 (8.71), 1.192(4.39), 1.987 (16.00), 2.297 (4.76), 2.314 (6.89), 2.331 (5.14), 3.577(4.62), 3.590 (8.77), 3.606 (8.06), 3.634 (2.43), 4.020 (4.03), 4.037(3.96), 4.815 (3.11), 4.827 (3.16), 4.845 (3.08), 4.859 (2.88), 7.325(3.46), 7.334 (7.37), 7.356 (6.87), 7.380 (2.99), 7.399 (5.75), 7.420(4.45), 7.526 (13.43), 7.546 (9.83), 7.555 (3.20), 7.811 (2.87), 7.826(2.86), 8.595 (6.46), 8.617 (6.25), 8.754 (11.28), 10.157 (2.54), 10.171(4.84).

In analogy to Example 182, the example compound shown in Table 21 wasprepared, by reacting the compound from Example 72A with the appropriateamines (or salts thereof) under the reaction conditions described.Differences are specified in the respective examples.

TABLE 21 Ex. Analytical data 183

LC-MS (Method 1): R_(t) = 1.00 min; m/z = 559.1 [M + H]⁺. ¹H-NMR (400MHz, DMSO-d₆) δ [ppm]: 2.83-3.00 (m, 1H), 3.42-3.52 (m, 1H), 3.56- 3.73(m, 1H), 4.24-4.30 (m, 1H), 4.78-4.90 (m, 2H), 5.25-5.29 (m, 0.5H),5.31-5.36 (m, 0.5H), 7.33-7.43 (m, 2H), 7.54 (d, 1H), 7.56- 7.66 (m,1H), 8.44-8.52 (m, 1H), 8.66 (d, 1H), 8.79 (s, 1H), 10.13-10.19 (m, 1H).

Example 1841-(2,4-Difluorophenyl)-N-[2-(2,6-difluorophenyl)propan-2-yl]-4-oxo-7-(2-oxoimidazolidin-1-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

5 mg (0.02 mmol) of palladium(II) acetate and 13 mg (0.02 mmol) ofXantphos were stirred in 2.7 ml of dioxane under an argon atmosphere at20° C. for 10 minutes. Then 150 mg (0.23 mmol, 75% purity) of thecompound from Example 71A, 40 mg (0.46 mmol) of 2-imidazolidinone and112 mg (0.35 mmol) of caesium carbonate were added and the mixture wasstirred at 110° C. for 6 h. After cooling down to 23° C., the mixturewas purified via preparative HPLC (eluent: acetonitrile/water gradientwith 0.1% formic acid). This gave 45 mg (35% of theory) of the titlecompound.

LC-MS (Method 1): R_(t)=1.00 min; m/z=540.2 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 1.839 (16.00), 1.987 (1.18), 3.534(1.12), 3.555 (1.83), 3.576 (1.84), 6.942 (2.23), 6.963 (3.18), 6.989(2.62), 7.248 (1.08), 7.269 (1.75), 7.275 (1.24), 7.284 (1.63), 7.289(1.21), 7.304 (1.85), 7.556 (1.46), 7.607 (3.76), 7.810 (1.62), 7.825(1.63), 8.387 (3.80), 8.409 (4.82), 8.546 (4.78), 8.568 (4.25), 8.575(7.71), 10.534 (4.55).

In analogy to Example 184, the example compound shown in Table 22 wasprepared, by reacting the compound from Example 71A with the appropriateamines (or salts thereof) under the reaction conditions described.Differences are specified in the respective examples.

TABLE 22 Ex. Analytical data 185

LC-MS (Method 1): R_(t) = 1.16 min MS (ESpos): m/z = 575.3 [M + H]⁺¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 1.157 (4.28), 1.175 (8.38), 1.193(4.21), 1.842 (10.49), 1.989 (16.00), 2.302 (1.66), 2.319 (2.48), 2.336(1.72), 3.576 (1.42), 3.595 (2.93), 3.613 (2.62), 3.624 (1.78), 3.642(0.79), 4.003 (1.40), 4.021 (3.96), 4.039 (3.85), 4.057 (1.24), 6.946(1.55), 6.967 (2.19), 6.992 (1.69), 7.251 (0.78), 7.256 (0.76), 7.271(1.60), 7.292 (1.53), 7.309 (0.73), 7.363 (2.74), 7.385 (2.84), 7.507(0.64), 7.513 (0.65), 7.535 (0.99), 7.555 (0.61), 7.562 (0.57), 7.795(0.70), 7.801 (1.09), 7.816 (1.08), 7.823 (0.60), 8.597 (5.07), 8.650(2.78), 8.672 (2.60), 10.470 (2.95).

Example 1861-(2,4-Difluorophenyl)-4-oxo-7-(2-oxoimidazolidin-1-yl)-N-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

A mixture of 200 mg (0.4 mmol) of the compound from Example 65A, 147 mg(1.7 mmol) of 2-imidazolidinone, 118 mg (0.9 mmol) of potassiumcarbonate, 83 mg (0.4 mmol) of copper(I) iodide and 32 mg (0.4 mmol) oftrans-N,N′-dimethyl-1,2-cyclohexanediamine in 5 ml of DMF was stirred at110° C. for 22 h. Subsequently, the mixture was filtered and thefiltrate was purified via preparative HPLC (eluent: acetonitrile/watergradient with 0.1% formic acid). This gave 7 mg (3% of theory) of thetitle compound.

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.150 (1.07), −0.009 (9.84), 0.007(8.65), 0.146 (1.15), 1.677 (7.23), 2.068 (16.00), 2.327 (0.71), 2.365(0.96), 2.669 (0.75), 2.709 (0.97), 3.563 (0.92), 7.341 (0.77), 7.601(2.15), 7.836 (0.93), 7.851 (0.93), 8.144 (0.84), 8.368 (2.57), 8.391(3.21), 8.515 (3.29), 8.537 (2.43), 8.638 (4.84), 9.797 (2.58).

LC-MS (Method 1): R_(t)=1.21 min

MS (ESpos): m/z=520.2 [M+H]⁺

Example 1871-(2,4-Difluorophenyl)-7-[4-fluoro-2-oxopyrrolidin-1-yl]-4-oxo-N-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

To 150 mg (0.28 mmol) of the compound from Example 170 in 5 ml of DCM at−78° C. were added dropwise 143 mg (0.84 mmol) of DAST, and the mixturewas stirred at −78° C. for 3 hours. Then the mixture was warmed to 20°C. and saturated aqueous sodium chloride solution was added. The productwas extracted with ethyl acetate. The solvent was removed under reducedpressure and the residue was purified directly via preparative HPLC(eluent: acetonitrile/water gradient with 0.1% formic acid). This gave 6mg (4% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.31 min; m/z=537.4 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ=1.67 (br. s, 6H), 2.07 (br.s, 9H),2.73-2.83 (m), 3.7-3.9 (m), 3.94-4.04 (m), 4.48-4.59 (m, 1H), 5.30-5.36(m), 5.43-5.48 (m), 7.11 (d, 1H), 7.31-7.42 (m, 1H), 7.57-7.73 (m, 1H),7.83-7.91 (m, 1H), 8.44-8.49 (m, 1H), 8.69-8.74 (m, 2H), 9.70 (br. s,1H).

Example 1887-[(3R)-3-(Difluoromethoxy)pyrrolidin-1-yl]-1-(2,4-difluorophenyl)-N-[2-(2,6-difluorophenyl)propan-2-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide

400 mg (0.74 mmol) of the compound from Example 21 and 71 mg (0.37 mmol)of copper(I) iodide were initially charged in 11 ml of acetonitrileunder an argon atmosphere. Added dropwise to this mixture at 55C were asolution of 264 mg (1.48 mmol) of 2,2-difluoro-2-(fluorosulphonyl)aceticacid in 6 ml of acetonitrile, and the mixture was then stirred at 55Cfor 20 minutes. Then a further 528 mg (3 mmol) of2,2-difluoro-2-(fluorosulphonyl)acetic acid in 29 ml of acetonitrilewere added dropwise, and the mixture was then stirred at 55° C. for 6hours. The solvent was removed under reduced pressure and the residuewas purified by preparative HPLC (in three portions; eluent:acetonitrile/water gradient with 0.1% formic acid). This gave 121 mg(28% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.24 min; m/z=591.4 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 0.006 (0.90), 1.156 (1.80), 1.174(3.60), 1.192 (1.83), 1.826 (16.00), 1.987 (6.86), 2.147 (0.58), 2.365(0.31), 2.709 (0.28), 3.493 (0.35), 3.590 (0.46), 4.002 (0.54), 4.020(1.61), 4.037 (1.60), 4.055 (0.52), 4.844 (0.36), 4.933 (0.27), 6.549(0.46), 6.739 (0.96), 6.771 (1.40), 6.793 (1.37), 6.936 (2.38), 6.958(3.19), 6.983 (2.59), 6.995 (0.39), 7.227 (0.45), 7.242 (1.03), 7.248(1.00), 7.263 (2.26), 7.278 (2.13), 7.283 (2.14), 7.299 (1.07), 7.508(0.75), 7.514 (0.77), 7.536 (1.28), 7.556 (0.76), 7.563 (0.71), 7.739(0.59), 7.760 (1.20), 7.776 (1.19), 7.797 (0.54), 8.132 (0.39), 8.314(2.17), 8.336 (2.09), 8.420 (6.84), 10.672 (4.67).

Example 1891-(2,4-Difluorophenyl)-7-[(3S)-3-fluoropyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP3, 100 mg (224 μmol) of the compound from Example 67Awere reacted with 34 mg (0.27 mmol) of (S)-3-fluoropyrrolidinehydrochloride and 0.14 ml (0.79 mmol) of N,N-diisopropylethylamine in 1ml of dimethylformamide. The crude product was diluted with 0.5 ml ofacetonitrile and purified by means of preparative HPLC (column:Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05% formicacid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90% acetonitrileand a further 3 min. 90% acetonitrile), and 97.5 mg (86% of theory, 99%purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.49 (d, 1H), 8.63 (s, 1H), 8.33 (d,1H), 7.86-7.78 (m, 1H), 7.63-7.53 (m, 1H), 7.36-7.29 (m, 1H), 6.85-6.77(m, 1H), 5.55-5.23 (m, 1H), 4.80-4.67 (m, 1H), 3.85-3.05 (m, 4H),2.33-1.97 (m, 2H), 1.93-1.82 (m, 1H), 1.70-1.57 (m, 1H), 0.97 (t, 3H).

LC-MS (Method 1): R_(t)=1.22 min; 499 [M+H]⁺.

Example 1901-(2,4-Difluorophenyl)-7-[(1R,5S)-6-(methoxymethyl)-3-azabicyclo[3.1.0]hex-3-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP3, 100 mg (224 μmol) of the compound from Example 67Awere reacted with 44 mg (0.27 mmol) of(1R,5S)-6-(methoxymethyl)-3-azabicyclo[3.1.0]hexane hydrochloride and0.14 ml (0.79 mmol) of N,N-diisopropylethylamine in 2.2 ml ofdimethylformamide. The crude product was diluted with acetonitrile andpurified by means of preparative HPLC (column: Chromatorex C18, 10 μm,125×30 mm, solvent: acetonitrile/0.05% formic acid gradient; (0 to 3min. 10% acetonitrile to 35 min. 90% acetonitrile and a further 3 min.90% acetonitrile), and 107 mg (89% of theory, 99% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=10.49 (d, 1H), 8.62 (s, 1H), 8.28 (d,1H), 7.84-7.76 (m, 1H), 7.64-7.53 (m, 1H), 7.36-7.28 (m, 1H), 6.73 (d,1H), 4.79-4.66 (m, 1H), 3.73-3.11 (m, 6H), 3.20 (s, 3H), 1.94-1.82 (m,1H), 1.71-1.50 (m, 3H), 0.96 (t, 3H), 0.85-0.74 (m, 1H).

LC-MS (Method 3): R_(t)=2.29 min; 537 [M+H]⁺.

Example 1911-(2,4-Difluorophenyl)-7-[3-methoxy-3-methylpyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP3, 100 mg (224 μmol) of the compound from Example 67Awere reacted with 43 mg (0.27 mmol) of rac-3-methoxy-3-methylpyrrolidinehydrochloride and 0.14 ml (0.79 mmol) of N,N-diisopropylethylamine in2.2 ml of dimethylformamide. The crude product was diluted withacetonitrile and purified by means of preparative HPLC (column:Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05% formicacid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90% acetonitrileand a further 3 min. 90% acetonitrile), and 105 mg (89% of theory, 99%purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.51 (d, 1H), 8.61 (s, 1H),8.31-8.24 (m, 1H), 7.86-7.76 (m, 1H), 7.64-7.52 (m, 1H), 7.37-7.28 (m,1H), 6.74 (d, 1H), 4.80-4.67 (m, 1H), 3.63-2.83 (m, 7H), 2.24-2.01 (m,1H), 1.94-1.57 (m, 3H), 1.35-1.20 (2×s, 3H), 0.97 (t, 3H).

LC-MS (Method 3): R_(t)=2.30 min; 525 [M+H]⁺.

Example 1921-(2,4-Difluorophenyl)-4-oxo-7-(pyrrolidin-1-yl)-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 100 mg (269 μmol) of the compound from Example 57Awere reacted with 66.1 mg (40.4 μmol) of(2R)-1,1,1-trifluorobutan-2-amine hydrochloride in the presence of 102mg (269 μmol) of HATU and 153 μl (876 μmol) of N,N-diisopropylethylaminein 2.7 ml of dimethylformamide. After purification by means ofpreparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm, solvent:acetonitrile/0.05% formic acid gradient; (0 to 3 min. 10% acetonitrileto 35 min. 90% acetonitrile and a further 3 min. 90% acetonitrile), 24mg (19% of theory, 100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.53 (d, 1H), 8.60 (s, 1H), 8.28 (d,1H), 7.85-7.75 (m, 1H), 7.61-7.52 (m, 1H), 7.35-7.27 (m, 1H), 6.75 (d,1H), 4.80-4.68 (m, 1H), 3.51-3.34 (br. s, 2H), 3.21-3.02 (br. s, 2H),1.99-1.74 (m, 5H), 1.70-1.56 (m, 1H), 0.97 (t, 3H).

LC-MS (Method 1): R_(t)=1.31 min; 481 [M+H]⁺.

Example 1931-(2,4-Difluorophenyl)-7-[(4S)-4-methoxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

To a solution of 50 mg (98 μmol) of the compound from Example 175 in 1ml of DCM were added 24 μl (0.39 mmol, 4 eq.) of methyl iodide and 270mg (2.11 mmol, 21.5 eq.) of silver(I) oxide, and the resultingsuspension was stirred at room temperature for 1 d and under reflux for3 d. Subsequently, the mixture was cooled to RT and the crude productwas purified by means of preparative HPLC (column: Chromatorex C18, 10μm, 125×30 mm, solvent: acetonitrile/0.05% formic acid gradient; (0 to 3min. 10% acetonitrile to 35 min. 90% acetonitrile and a further 3 min.90% acetonitrile)), and 28.4 mg (55% of theory, 99% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.21 (d, 1H), 8.87 (d, 1H), 8.72 (d,1H), 8.49 (d, 1H), 7.92-7.84 (m, 1H), 7.71-7.59 (m, 1H), 7.42-7.33 (m,1H), 4.83-4.71 (m, 1H), 4.06-4.00 (m, 1H), 3.74-3.54 (m, 2H), 3.22/3.17(2×s, 3H), 3.01-2.90 (m, 1H), 2.64-2.56 (m, 1H), 1.96-1.83 (m, 1H),1.73-1.60 (m, 1H), 0.98 (t, 3H).

LC-MS (Method 1): R_(t)=1.11 min; 525 [M+H]⁺.

Example 1941-(2,4-Difluorophenyl)-7-[3-hydroxy-3-methyl-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP2, 163 mg (366 μmol) of the compound from Example 67Awere reacted with 42.1 mg (366 μmol) of the compound from Example 2A inthe presence of 179 mg (548 μmol) of caesium carbonate, 15 mg (66 μmol)of palladium(II) acetate and 38 mg (66 μmol) of Xantphos in 8.2 ml ofdioxane. After purification by means of flash chromatography (twice,ethyl acetate/cyclohexane gradient), 153.6 mg (75% of theory, 94%purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.21 (d, 1H), 8.87 (s, 1H), 8.74 (d,1H), 8.54 (d, 1H), 7.92-7.84 (m, 1H), 7.66-7.58 (m, 1H), 7.40-7.30 (m,1H), 5.72 (d, 1H), 4.84-4.70 (m, 1H), 3.60-3.49 (m, 1H), 3.45-3.34 (m,1H), 2.06-1.85 (m, 3H), 1.72-1.62 (m, 1H), 1.29/1.27 (2×s, 3H), 0.98 (t,3H).

LC-MS (Method 3): R_(t)=1.95 min; 525 [M+H]⁺.

130 mg of the title compound (diastereomer mixture) were separated intothe diastereomers by chiral HPLC (preparative HPLC: column: Daicel®Chiralpak AD-H, 5 μm, 250×20 mm; eluent: 85% CO₂/15% isopropanol; flowrate 80 ml/min; 40° C., detection: 210 nm).

This gave (in the sequence of elution from the column) 37.2 mg ofdiastereomer 1 (99% de) R_(t)=6.04 min and 32.7 mg (99% de) ofdiastereomer 2 R_(t)=7.33 min.

[Analytical HPLC: column: SFC Daicel® Chiralpak AD, 3 ml/min; 90%CO₂/10% isopropanol]

Diastereomer 1 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90%acetonitrile and a further 3 min. 90% acetonitrile)), and 24.6 mg (13%of theory, 99% purity) of the title compound from Example 196 wereobtained.

Diastereomer 2 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90%acetonitrile and a further 3 min. 90% acetonitrile)), and 20.6 mg (11%of theory, 99% purity) of the title compound from Example 197 wereobtained.

Example 1951-(2,4-Difluorophenyl)-7-[3-hydroxy-3-methyl-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.21 (d, 1H), 8.86 (s, 1H), 8.74 (d,1H), 8.54 (d, 1H), 7.92-7.84 (m, 1H), 7.67-7.58 (m, 1H), 7.40-7.32 (m,1H), 5.72 (d, 1H), 4.83-4.71 (m, 1H), 3.60-3.49 (m, 1H), 3.45-3.34 (m,1H), 2.07-1.84 (m, 3H), 1.74-1.60 (m, 1H), 1.29/1.27 (2×s, 3H), 0.98 (t,3H).

LC-MS (Method 1): R_(t)=1.04 min; 525 [M+H]⁺.

Example 1961-(2,4-Difluorophenyl)-7-[3-hydroxy-3-methyl-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.21 (d, 1H), 8.86 (s, 1H), 8.74 (d,1H), 8.54 (d, 1H), 7.92-7.84 (m, 1H), 7.66-7.59 (m, 1H), 7.39-7.33 (m,1H), 5.72 (d, 1H), 4.82-4.72 (m, 1H), 3.60-3.49 (m, 1H), 3.45-3.34 (m,1H), 2.05-1.85 (m, 3H), 1.71-1.59 (m, 1H), 1.29/1.27 (2×s, 3H), 0.98 (t,3H).

LC-MS (Method 1): R_(t)=1.04 min; 525 [M+H]⁺.

Example 1971-(2,4-Difluorophenyl)-7-[3-methoxy-3-methyl-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

To a solution of 30 mg (57 μmol) of the diastereomer mixture fromExample 194 in 1 ml of DCM were added 28 μl (0.46 mmol, 8 eq.) of methyliodide and 170 mg (1.37 mmol, 24 eq.) of silver(I) oxide, and theresulting suspension was stirred under reflux for 3 d. Subsequently, themixture was cooled to RT and filtered, and 30.0 mg (96% of theory, 99%purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.20 (d, 1H), 8.87 (s, 1H), 8.75 (d,1H), 8.54 (d, 1H), 7.91-7.83 (m, 1H), 7.66-7.58 (m, 1H), 7.41-7.33 (m,1H), 4.83-4.73 (m, 1H), 3.53-3.39 (m, 2H), 3.21/3.18 (2×s, 3H),2.29-2.17 (m, 1H), 2.01-2.84 (m, 2H), 1.73-1.61 (m, 1H), 1.33/1.31 (2×s,3H), 0.98 (t, 3H).

LC-MS (Method 3): R_(t)=2.24 min; 539 [M+H]⁺.

30 mg of the title compound (diastereomer mixture) were separated intothe diastereomers by chiral HPLC (preparative HPLC: Chiralpak-IF 5 m250×20 mm; eluent: 100% methanol, 0.2% diethylamine; temperature: 30°C.; flow rate: 15 ml/min; UV detection: 220 nm).

This gave (in the sequence of elution from the column) 11 mg ofdiastereomer 1 (99% de) R_(t)=7.26 min and 6 mg (97.4% de) ofdiastereomer 2 R_(t)=8.36 min.

[Analytical HPLC: column: Chiralpak IF 5 m 250×4.6 mm; eluent: 100%methanol, 0.2% diethylamine; temperature: 40° C.; flow rate: 1 ml/min;UV detection: 235 nm]

Diastereomer 1 was additionally purified (column: Chromatorex C18, 10 m,125×30 mm, solvent: acetonitrile/0.05% formic acid gradient; (0 to 3min. 10% acetonitrile to 35 min. 90% acetonitrile and a further 3 min.90% acetonitrile)), and 6.4 mg (21% of theory, 99% purity) of the titlecompound from Example 198 were obtained.

Diastereomer 2 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90%acetonitrile and a further 3 min. 90% acetonitrile)), and 3.6 mg (12% oftheory, 99% purity) of the title compound from Example 199 wereobtained.

Example 1981-(2,4-Difluorophenyl)-7-[3-methoxy-3-methyl-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.19 (d, 1H), 8.87 (s, 1H), 8.75 (d,1H), 8.54 (d, 1H), 7.91-7.83 (m, 1H), 7.66-7.58 (m, 1H), 7.39-7.33 (m,1H), 4.84-4.70 (m, 1H), 3.60-3.38 (m, 2H), 3.20/3.18 (2×s, 3H),2.28-2.17 (m, 1H), 2.02-1.84 (m, 2H), 1.74-1.60 (m, 1H), 1.33/1.31 (2×s,3H), 0.98 (t, 3H).

LC-MS (Method 3): R_(t)=2.26 min; 539 [M+H]⁺.

Example 1991-(2,4-Difluorophenyl)-7-[3-methoxy-3-methyl-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.19 (d, 1H), 8.87 (s, 1H), 8.75 (d,1H), 8.54 (d, 1H), 7.91-7.83 (m, 1H), 7.65-7.59 (m, 1H), 7.39-7.33 (m,1H), 4.83-4.72 (m, 1H), 3.60-3.37 (m, 2H), 3.21/3.18 (2×s, 3H),2.28-2.17 (m, 1H), 2.01-1.84 (m, 2H), 1.72-1.60 (m, 1H), 1.33/1.31 (2×s,3H), 0.98 (t, 3H).

LC-MS (Method 3): R_(t)=2.24 min; 539 [M+H]⁺.

Example 200(3S)-1-[8-(2,4-Difluorophenyl)-5-oxo-6-{[(2R)-1,1,1-trifluorobutan-2-yl]carbamoyl}-5,8-dihydro-1,8-naphthyridin-2-yl]-5-oxopyrrolidin-3-ylmethyl carbamate

To a solution of 100 mg (196 μmol) of the compound from Example 175 in 4ml of DCM were added 18.3 mg (196 μmol) of methylcarbamoyl chloride, 4.8mg (39 μmol) of 4-dimethylaminopyridine and 30 μl (0.22 mmol) oftriethylamine, and the mixture was stirred at RT overnight. The solventwas then removed under reduced pressure and the residue was purified bymeans of preparative HPLC (column: Kromasil C18, 10 μm, 125×30 mm,solvent: acetonitrile/0.05% formic acid gradient (0 to 3 min 10%acetonitrile, to 35 min 90% acetonitrile and for a further 3 min 90%acetonitrile)). 31.9 mg (28% of theory, 99% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.20 (d, 1H), 8.88-8.85 (m, 1H),8.73 (d, 1H), 8.51-8.45 (m, 1H), 7.91-7.81 (m, 1H), 7.66-7.55 (m, 1H),7.41-7.32 (m, 1H), 7.22-7.08 (m, 1H), 5.15-5.09 (m, 1H), 4.84-4.71 (m,1H), 3.89-3.77 (m, 1H), 3.68-3.54 (m, 1H), 3.20-3.09 (m, 1H), 1.96-1.84(m, 1H), 1.73-1.60 (m, 1H), 0.98 (t, 3H).

LC-MS (Method 4): R_(t)=3.27 min; 568 [M+H]⁺.

Example 201N-(2,6-Dichlorophenyl)-1-(2,4-difluorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 100 mg (153 μmol, 73.6% purity) of the compound fromExample 81A were reacted with 15.5 mg (153 μmol) of(4S)-4-hydroxypyrrolidin-2-one in the presence of 74.8 mg (230 μmol) ofcaesium carbonate, 6.2 mg (28 μmol) of palladium(II) acetate and 16 mg(28 μmol) of Xantphos in 2 ml of dioxane. The residue was purified bymeans of flash chromatography (cyclohexane/ethyl acetate gradient) andfinally by preparative thin-layer chromatography(dichloromethane/methanol=95/5, 20×20 cm plates, 1 mm of silica). Theproduct fraction was visualized by UV detection and scratched off, andeluted from the silica gel with ethyl acetate. The mixture was filteredthrough Celite and the solvent was removed under reduced pressure. Theresidue was lyophilized from water/acetonitrile, and 27.3 mg (33% oftheory; 100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=11.7 (s, 1H), 8.92 (s, 1H), 8.77 (d,1H), 8.57-8.52 (m, 1H), 7.96-7.86 (m, 1H), 7.67-7.57 (m, 3H), 7.42-7.33(m, 2H), 5.33 (dd, 1H), 4.32-4.25 (m, 1H), 3.74-3.63 (m, 1H), 3.54-3.43(m, 1H), 3.01-2.89 (m, 1H), 2.43-2.31 (m, 1H).

LC-MS (Method 1): R_(t)=1.03 min; 545 [M+H]⁺.

Example 202N-(2,6-Dichlorophenyl)-1-(2,4-difluorophenyl)-7-[(3S)-3-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 150 mg (275 μmol, 88% purity) of the compound fromExample 81A were reacted with 27.8 mg (275 μmol) of(3S)-3-hydroxypyrrolidin-2-one in the presence of 56.9 mg (412 μmol) ofpotassium carbonate, 6.2 mg (27 μmol) of palladium(II) acetate and 32 mg(55 μmol) of Xantphos in 2.8 ml of dioxane. The crude product waspurified twice by means of preparative HPLC (column: Chromatorex C18, 10μm, 125×30 mm, solvent: acetonitrile/0.05% formic acid gradient (0 to 3min 10% acetonitrile, to 35 min 90% acetonitrile and for a further 3 min90% acetonitrile). 49.2 mg (33% of theory, 100% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.69 (s, 1H), 8.93 (s, 1H), 8.79 (d,1H), 8.58-8.52 (m, 1H), 7.94-7.85 (m, 1H), 7.66-7.57 (m, 3H), 7.42-7.32(m, 2H), 5.91 (d, 1H), 4.46-4.34 (m, 1H), 3.64-3.51 (m, 1H), 3.39-3.27(m, 1H), 2.38-2.27 (m, 1H), 1.86-1.69 (m, 1H).

LC-MS (Method 3): R_(t)=1.83 min; 545 [M+H]⁺.

Example 2037-(Dimethylamino)-1-(2-fluorophenyl)-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 100 mg (306 μmol) of the compound from Example 62Awere reacted with 58.3 mg (458 μmol) of (S)-2-trifluoromethylpropylaminein the presence of 116 mg (306 μmol) of HATU and 160 μl (917 μmol) ofN,N-diisopropylethylamine in 3.2 ml of dimethylformamide. The reactionwas ended by adding aqueous 1 M hydrochloric acid and 10 ml of water,and the precipitate was filtered off with suction. The precipitatedsolid was washed with water and dried under high vacuum overnight. Theresidue was taken up in 2 ml of dichloromethane and purified by means offlash chromatography (cyclohexane/ethyl acetate gradient), and 87.4 mg(65% of theory; 99% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.51 (d, 1H), 8.59 (s, 1H), 8.29 (d,1H), 7.77-7.69 (m, 1H), 7.66-7.59 (m, 1H), 7.52-7.46 (m, 1H), 7.45-7.39(m, 1H), 6.94 (d, 1H), 4.80-4.66 (m, 1H), 2.93 (br. s, 6H), 1.94-1.82(m, 1H), 1.71-1.56 (m, 1H), 0.97 (t, 3H).

LC-MS (Method 3): R_(t)=2.18 min; 437 [M+H]⁺.

Example 204rac-7-(Dimethylamino)-1-(2-fluorophenyl)-4-oxo-N-[1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 100 mg of the compound from Example 62A were reactedwith 75.0 mg (458 μmol) of rac-2-trifluoromethylpropylaminehydrochloride in the presence of 116 mg (306 μmol) of HATU and 160 μl(917 μmol) of N,N-diisopropylethylamine in 3.2 ml of dimethylformamide.The reaction was ended by adding aqueous 1 M hydrochloric acid and 10 mlof water, and the precipitate was filtered off with suction. Theprecipitated solid was washed with water and dried under high vacuumovernight. The residue was taken up in 2 ml of dichloromethane andpurified by means of flash chromatography (cyclohexane/ethyl acetategradient), and 98.6 mg (73% of theory; 99% purity) of the title compoundwere obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.51 (d, 1H), 8.59 (s, 1H), 8.29 (d,1H), 7.76-7.69 (m, 1H), 7.66-7.59 (m, 1H), 7.52-7.46 (m, 1H), 7.45-7.39(m, 1H), 6.94 (d, 1H), 4.80-4.68 (m, 1H), 2.93 (br. s, 6H), 1.93-1.84(m, 1H), 1.69-1.58 (m, 1H), 0.97 (t, 3H).

LC-MS (Method 3): R_(t)=2.14 min; 437 [M+H]⁺.

Example 2051-(2,4-Difluorophenyl)-4-oxo-7-(2-oxoazetidin-1-yl)-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 100 mg (224 μmol) of the compound from Example 67Awere reacted with 15.9 mg (224 μmol) of azetidinone in the presence of11.6 mg (0.011 mmol) of tris(dibenzylidenacetone)dipalladium-chloroformcomplex and 19 mg (34 μmol) of Xantphos in 5 ml of toluene at 90° C. Thecrude product was purified by flash chromatography (cyclohexane/ethylacetate gradient) and preparative HPLC (column: Chromatorex C18, 10 μm,125×30 mm, solvent: acetonitrile/0.05% formic acid gradient (0 to 3 min10% acetonitrile, to 35 min 90% acetonitrile and for a further 3 min 90%acetonitrile). 18.5 mg (17% of theory, 99% purity) of the title compoundwere obtained.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=10.20 (d, 1H), 8.83 (s, 1H), 8.69 (d,1H), 7.90-7.82 (m, 1H), 7.74 (d, 1H), 7.64-7.57 (m, 1H), 7.39-7.31 (m,1H), 4.83-4.71 (m, 1H), 3.45-3.35 (m, 2H), 3.14-3.07 (m, 2H), 1.95-1.83(m, 1H), 1.73-1.59 (m, 1H), 0.97 (t, 3H).

LC-MS (Method 3): R_(t)=2.15 min; 481 [M+H]⁺.

Example 206rac-N-[(1R)-(2-Chlorophenyl)-2,2,2-trifluoroethyl]-1-(2,4-difluorophenyl)-7-[3-hydroxy-2-oxopiperidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP2, 150 mg (273 μmol, 96% purity) of the compound fromExample 73A were reacted with 31.4 mg (273 μmol) of3-hydroxy-2-piperidone in the presence of 56.5 mg (409 μmol) ofpotassium carbonate, 6.1 mg (27 μmol) of palladium(II) acetate and 32 mg(55 μmol) of Xantphos in 2.7 ml of dioxane. The residue was purified byflash chromatography (cyclohexane/ethyl acetate gradient) andpreparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm, solvent:acetonitrile/0.05% formic acid gradient (0 to 3 min 10% acetonitrile, to35 min 90% acetonitrile and for a further 3 min 90% acetonitrile). 69.8mg (42% of theory, 100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.29 (d, 1H), 8.88 (s, 1H), 8.70 (d,1H), 8.19-8.10 (m, 1H), 7.93-7.77 (m, 1H), 7.67-7.48 (m, 5H), 7.40-7.31(m, 1H), 6.53-6.42 (m, 1H), 5.53-5.46 (m, 1H), 4.27-4.18 (m, 1H),3.71-3.59 (m, 1H), 3.54-3.41 (m, 1H), 2.12-2.02 (m, 1H), 1.84-1.73 (m,2H), 1.71-1.58 (m, 1H).

LC-MS (Method 3): R_(t)=2.18 min; 607 [M+H]⁺.

58 mg of the title compound (racemic diastereomer mixture) wereseparated into the enantiomeric diastereomers by chiral HPLC(preparative HPLC: column: Chiralcel OZ-H 5 m 250×20 mm; eluent: 75%ethanol, 25% isohexane; temperature: 40° C.; flow rate: 15 ml/min; UVdetection: 220 nm).

This gave (in the sequence of elution from the column) 14 mg ofdiastereomer 1 (enantiomer A) (99% de) R_(t)=6.63 min, 12 mg (99% de) ofdiastereomer 2 (enantiomer A) R_(t)=7.71 min, 11 mg (99% de) ofdiastereomer 1 (enantiomer B) R_(t)=12.9 min, and 18 mg (99% de) ofdiastereomer 2 (enantiomer B) R_(t)=18.3 min.

[Analytical HPLC: column: Chiralcel OZ-H 5 m 250×4.6 mm; eluent: 75%ethanol, 25% isohexane; temperature: 40° C.; flow rate: 1 ml/min; UVdetection: 220 nm]

Diastereomer 1 (enantiomer A) was additionally purified by means ofpreparative HPLC (column: Chromatorex C18, 10 m, 125×30 mm, solvent:acetonitrile/0.05% formic acid gradient; (0 to 3 min. 10% acetonitrileto 35 min. 90% acetonitrile and a further 3 min. 90% acetonitrile)), and10.4 mg (6.2% of theory, 99% purity) of the title compound from Example207 were obtained.

Diastereomer 2 (enantiomer A) was additionally purified by means ofpreparative HPLC (column: Chromatorex C18, 10 m, 125×30 mm, solvent:acetonitrile/0.05% formic acid gradient; (0 to 3 min. 10% acetonitrileto 35 min. 90% acetonitrile and a further 3 min. 90% acetonitrile)), and8.4 mg (5% of theory, 99% purity) of the title compound from Example 208were obtained.

Diastereomer 1 (enantiomer B) was additionally purified by means ofpreparative HPLC (column: Chromatorex C18, 10 m, 125×30 mm, solvent:acetonitrile/0.05% formic acid gradient; (0 to 3 min. 10% acetonitrileto 35 min. 90% acetonitrile and a further 3 min. 90% acetonitrile)), and8.7 mg (5% of theory, 99% purity) of the title compound from Example 209were obtained.

Diastereomer 2 (enantiomer B) was additionally purified by means ofpreparative HPLC (column: Chromatorex C18, 10 m, 125×30 mm, solvent:acetonitrile/0.05% formic acid gradient; (0 to 3 min. 10% acetonitrileto 35 min. 90% acetonitrile and a further 3 min. 90% acetonitrile)), and11.4 mg (6.8% of theory, 99% purity) of the title compound from Example210 were obtained.

Example 207N-[(1R)-1-(2-Chlorophenyl)-2,2,2-trifluoroethyl]-1-(2,4-difluorophenyl)-7-[3-hydroxy-2-oxopiperidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1, Enantiomer A)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.29 (d, 1H), 8.88 (s, 1H), 8.70 (d,1H), 8.18-8.11 (m, 1H), 7.92-7.77 (m, 1H), 7.67-7.48 (m, 5H), 7.40-7.31(m, 1H), 6.53-6.43 (m, 1H), 5.52-5.47 (m, 1H), 4.26-4.18 (m, 1H),3.72-3.59 (m, 1H), 3.52-3.41 (m, 1H), 2.11-2.02 (m, 1H), 1.84-1.73 (m,2H), 1.71-1.58 (m, 1H).

LC-MS (Method 3): R_(t)=2.21 min; 607 [M+H]⁺.

Example 208N-[(1R)-1-(2-Chlorophenyl)-2,2,2-trifluoroethyl]-1-(2,4-difluorophenyl)-7-[3-hydroxy-2-oxopiperidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2, Enantiomer A)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.29 (d, 1H), 8.88 (s, 1H), 8.70 (d,1H), 8.18-8.11 (m, 1H), 7.91-7.78 (m, 1H), 7.67-7.48 (m, 5H), 7.40-7.31(m, 1H), 6.53-6.43 (m, 1H), 5.52-5.47 (m, 1H), 4.26-4.18 (m, 1H),3.72-3.59 (m, 1H), 3.52-3.41 (m, 1H), 2.11-2.02 (m, 1H), 1.84-1.73 (m,2H), 1.71-1.58 (m, 1H).

LC-MS (Method 3): R_(t)=2.21 min; 607 [M+H]⁺.

Example 209N-[(1R)-1-(2-Chlorophenyl)-2,2,2-trifluoroethyl]-1-(2,4-difluorophenyl)-7-[3-hydroxy-2-oxopiperidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1, Enantiomer B)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.29 (d, 1H), 8.88 (s, 1H), 8.70 (d,1H), 8.18-8.11 (m, 1H), 7.91-7.78 (m, 1H), 7.67-7.48 (m, 5H), 7.40-7.31(m, 1H), 6.53-6.43 (m, 1H), 5.52-5.47 (m, 1H), 4.26-4.18 (m, 1H),3.72-3.59 (m, 1H), 3.52-3.41 (m, 1H), 2.11-2.02 (m, 1H), 1.84-1.73 (m,2H), 1.71-1.58 (m, 1H).

LC-MS (Method 3): R_(t)=2.20 min; 607 [M+H]⁺.

Example 210N-[(1R)-1-(2-Chlorophenyl)-2,2,2-trifluoroethyl]-1-(2,4-difluorophenyl)-7-[3-hydroxy-2-oxopiperidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2, Enantiomer B)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.29 (d, 1H), 8.88 (s, 1H), 8.70 (d,1H), 8.18-8.11 (m, 1H), 7.92-7.77 (m, 1H), 7.67-7.48 (m, 5H), 7.40-7.31(m, 1H), 6.53-6.43 (m, 1H), 5.52-5.47 (m, 1H), 4.26-4.18 (m, 1H),3.72-3.59 (m, 1H), 3.52-3.41 (m, 1H), 2.11-2.02 (m, 1H), 1.84-1.73 (m,2H), 1.71-1.58 (m, 1H).

LC-MS (Method 3): R_(t)=2.21 min; 607 [M+H]⁺.

Example 211N-[1-(2-Chlorophenyl)-2,2,2-trifluoroethyl]-1-(2,4-difluorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP2, 750 mg (1.36 mmol, 96% purity) of the compound fromExample 73A were reacted with 138 mg (1.36 mmol) of(4S)-4-hydroxypyrrolidin-2-one in the presence of 283 mg (2.04 mmol) ofpotassium carbonate, 30.6 mg (136 μmol) of palladium(II) acetate and 158mg (273 μmol) of Xantphos in 14 ml of dioxane. The mixture was filtered,washed through with acetonitrile and concentrated, and the crude productwas purified by means of flash chromatography (cyclohexane/ethyl acetategradient). 555 mg (65% of theory, 95% purity) of the title compound wereobtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.33 (d, 1H), 8.86 (s, 1H), 8.75 (d,1H), 8.57-8.51 (m, 1H), 7.93-7.76 (m, 1H), 7.67-7.48 (m, 5H), 7.41-7.32(m, 1H), 6.53-6.42 (m, 1H), 5.37-5.27 (m, 1H), 4.31-4.25 (m, 1H),3.72-3.61 (m, 1H), 3.51-3.42 (m, 1H), 3.00-2.88 (m, 1H), 2.42-2.31 (m,1H).

LC-MS (Method 3): R_(t)=2.13 min; 593 [M+H]⁺.

550 mg of the title compound (diastereomer mixture) were separated intothe diastereomers by chiral HPLC (preparative HPLC: column: ChiralpakAZ-H 5 μm 250×20 mm; eluent: 50% isopropanol, 50% isohexane;temperature: 25° C.; flow rate: 15 ml/min; UV detection: 210 nm).

This gave (in the sequence of elution from the column) 229 mg ofdiastereomer 1 (99% de) R_(t)=0.96 min and 235 mg (99% de) ofdiastereomer 2 R_(t)=1.44 min.

[Analytical HPLC: column: Chiralcel AZ-3 3 μm 50×4.6 mm; eluent: 50%isopropanol, 50% isohexane; flow rate: 1 ml/min; UV detection: 220 nm]

Diastereomer 1 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90%acetonitrile and a further 3 min. 90% acetonitrile)), and 151.6 mg (19%of theory, 100% purity) of the title compound from Example 212 wereobtained.

Diastereomer 2 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90%acetonitrile and a further 3 min. 90% acetonitrile)), and 151.7 mg (19%of theory, 100% purity) of the title compound from Example 213 wereobtained.

Example 212N-[1-(2-Chlorophenyl)-2,2,2-trifluoroethyl]-1-(2,4-difluorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer A)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.33 (d, 1H), 8.86 (s, 1H), 8.75 (d,1H), 8.57-8.51 (m, 1H), 7.91-7.78 (m, 1H), 7.67-7.48 (m, 5H), 7.41-7.33(m, 1H), 6.52-6.42 (m, 1H), 5.32 (dd, 1H), 4.31-4.25 (m, 1H), 3.72-3.61(m, 1H), 3.51-3.41 (m, 1H), 3.00-2.88 (m, 1H), 2.41-2.31 (m, 1H).

LC-MS (Method 3): R_(t)=2.07 min; 593 [M+H]⁺.

Example 213N-[1-(2-Chlorophenyl)-2,2,2-trifluoroethyl]-1-(2,4-difluorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(diastereomer B)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.33 (d, 1H), 8.86 (s, 1H), 8.75 (d,1H), 8.57-8.51 (m, 1H), 7.93-7.76 (m, 1H), 7.67-7.48 (m, 5H), 7.42-7.32(m, 1H), 6.52-6.42 (m, 1H), 5.32 (dd, 1H), 4.31-4.25 (m, 1H), 3.71-3.61(m, 1H), 3.52-3.42 (m, 1H), 3.00-2.88 (m, 1H), 2.42-2.32 (m, 1H).

LC-MS (Method 3): R_(t)=2.07 min; 593 [M+H]⁺.

Example 2141-(2,4-Difluorophenyl)-N-[1-(2,6-difluorophenyl)ethyl]-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP1, 90 mg (0.15 mmol, 65% purity) of the compound fromExample 63A were reacted with 34.4 mg (219 μmol) ofrac-1-(2,6-difluorophenyl)ethylamine in the presence of 55.4 mg (146μmol) of HATU and 35.5 μl (204 μmol) of N,N-diisopropylethylamine in1.44 ml of dimethylformamide. The crude product was purified by means offlash chromatography (cyclohexane/ethyl acetate gradient), and 51.2 mg(65% of theory; 100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.54-10.48 (m, 1H), 8.75-8.67 (m,2H), 8.53-8.46 (m, 1H), 7.89-7.75 (m, 1H), 7.66-7.55 (m, 1H), 7.43-7.30(m, 2H), 7.16-7.05 (m, 2H), 5.68-5.56 (m, 1H), 5.35-5.26 (m, 1H),4.31-4.24 (m, 1H), 3.71-3.60 (m, 1H), 3.52-3.40 (m, 1H), 2.99-2.87 (m,1H), 2.40-2.31 (m, 1H), 1.57 (d, 3H).

LC-MS (Method 1): R_(t)=1.02 min; 541 [M+H]⁺.

39 mg of the title compound (diastereomer mixture) were separated intothe diastereomers by chiral HPLC (preparative HPLC: column: ChiralpakAZ-H 5 m 250×20 mm; eluent: 50% isopropanol, 50% isohexane; temperature:25° C.; flow rate: 15 ml/min; UV detection: 210 nm).

This gave (in the sequence of elution from the column) 14.9 mg ofdiastereomer 1 (99% de) R_(t)=1.14 min and 12.9 mg (99% de) ofdiastereomer 2 R_(t)=1.81 min.

[Analytical HPLC: column: Chiralcel AZ-3 3 m 50×4.6 mm; eluent: 50%isopropanol, 50% isohexane; flow rate: 1 ml/min; UV detection: 220 nm].

Diastereomer 1 was additionally purified by means of flashchromatography (cyclohexane/ethyl acetate gradient), and 14.3 mg (18% oftheory; 100% purity) of the compound from Example 215 were obtained.

Diastereomer 2 was additionally purified by means of flashchromatography (cyclohexane/ethyl acetate gradient), and 9.8 mg (12% oftheory; 100% purity) of the compound from Example 216 were obtained.

Example 2151-(2,4-Difluorophenyl)-N-[1-(2,6-difluorophenyl)ethyl]-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.54-10.49 (m, 1H), 8.75-8.69 (m,2H), 8.52-8.47 (m, 1H), 7.87-7.78 (m, 1H), 7.65-7.58 (m, 1H), 7.43-7.32(m, 2H), 7.15-7.07 (m, 2H), 5.68-5.56 (m, 1H), 5.35-5.25 (m, 1H),4.31-4.24 (m, 1H), 3.71-3.60 (m, 1H), 3.51-3.41 (m, 1H), 2.99-2.87 (m,1H), 2.40-2.31 (m, 1H), 1.57 (d, 3H).

LC-MS (Method 1): R_(t)=0.99 min; 541 [M+H]⁺.

Example 2161-(2,4-Difluorophenyl)-N-[1-(2,6-difluorophenyl)ethyl]-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.54-10.48 (m, 1H), 8.75-8.69 (m,2H), 8.53-8.47 (m, 1H), 7.90-7.76 (m, 1H), 7.66-7.56 (m, 1H), 7.43-7.31(m, 2H), 7.16-7.07 (m, 2H), 5.68-5.57 (m, 1H), 5.31 (dd, 1H), 4.31-4.24(m, 1H), 3.71-3.60 (m, 1H), 3.52-3.41 (m, 1H), 2.99-2.86 (m, 1H),2.41-2.31 (m, 1H), 1.57 (d, 3H).

LC-MS (Method 1): R_(t)=0.98 min; 541 [M+H]⁺.

Example 217N-[1-(2-Chlorophenyl)-2,2,2-trifluoroethyl]-1-(2,4-difluorophenyl)-7-[(3S)-3-fluoropyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP3, 150 mg (273 μmol, 96% purity) of the compound fromExample 73A were reacted with 41 mg (0.33 mmol) of(S)-3-fluoropyrrolidine hydrochloride and 0.21 ml (1.2 mmol) ofN,N-diisopropylethylamine in 2.7 ml of dimethylformamide. The crudeproduct was diluted with acetonitrile and purified by means ofpreparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm, solvent:acetonitrile/0.05% formic acid gradient; (0 to 3 min. 10% acetonitrileto 35 min. 90% acetonitrile and a further 3 min. 90% acetonitrile), and142 mg (90% of theory, 100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.62 (d, 1H), 8.64 (s, 1H), 8.37 (d,1H), 7.88-7.70 (m, 1H), 7.65-7.45 (m, 1H), 7.37-7.26 (m, 1H), 6.88-6.77(m, 1H), 6.50-6.40 (m, 1H), 5.55-5.23 (m, 1H), 3.84-3.06 (m, 4H),2.34-1.96 (m, 2H).

LC-MS (Method 3): R_(t)=2.40 min; 581 [M+H]⁺.

Example 2181-(2,4-Difluorophenyl)-7-[3-hydroxypyrrolidin-1-yl]-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP1, 250 mg (626 μmol) of the compound from Example 88Awere reacted with 154 mg (939 μmol) of (2R)-1,1,1-trifluorobutan-2-aminehydrochloride in the presence of 238 mg (626 μmol) of HATU and 153 μl(876 μmol) of N,N-diisopropylethylamine in 6.3 ml of dimethylformamide.After purification by means of flash chromatography (cyclohexane/ethylacetate gradient), 204 mg (66% of theory, 100% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.53 (d, 1H), 8.61 (s, 1H), 8.28 (d,1H), 7.86-7.75 (m, 1H), 7.61-7.53 (m, 1H), 7.36-7.28 (m, 1H), 6.80-6.70(m, 1H), 5.10-4.87 (m, 1H), 4.80-4.67 (m, 1H), 4.43.4.21 (m, 1H),3.60-3.01 (m, 4H), 2.09-1.56 (m, 4H), 0.97 (t, 3H).

LC-MS (Method 1): R_(t)=1.05 min; 497 [M+H]⁺.

169.9 mg of the title compound (diastereomer mixture) were separatedinto the diastereomers by chiral HPLC (preparative HPLC: separationmethod: column: Chiralcel OZ-H 5 m 250×20 mm; eluent: 25% isopropanol,75% isohexane; temperature: 30° C.; flow rate: 15 ml/min; UV detection:270 nm).

This gave (in the sequence of elution from the column) 88 mg ofdiastereomer 1 (99% de) R_(t)=5.35 min and 75 mg (97% de) ofdiastereomer 2 R_(t)=5.91 min.

[Analytical HPLC: column: Chiralcel OZ-H 5 m 250×4.6 mm; eluent: 30%isopropanol, 70% isohexane; temperature: 30° C.; flow rate: 1 ml/min; UVdetection: 270 nm]

Diastereomer 1 was additionally purified by means of flashchromatography (cyclohexane/ethyl acetate gradient), and 60 mg (19% oftheory; 97% purity) of the title compound from Example 219 wereobtained.

Diastereomer 2 was additionally purified by means of flashchromatography (cyclohexane/ethyl acetate gradient), and 46 mg (14% oftheory; 98% purity) of the title compound from Example 220 wereobtained.

Example 2191-(2,4-Difluorophenyl)-7-[3-hydroxypyrrolidin-1-yl]-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.52 (d, 1H), 8.61 (s, 1H), 8.28 (d,1H), 7.85-7.76 (m, 1H), 7.61-7.51 (m, 1H), 7.36-7.27 (m, 1H), 6.80-6.70(m, 1H), 5.09-4.88 (m, 1H), 4.80-4.67 (m, 1H), 4.42.4.21 (m, 1H),3.60-2.98 (m, 4H), 2.08-1.55 (m, 4H), 0.97 (t, 3H).

LC-MS (Method 1): R_(t)=1.01 min; 497 [M+H]⁺.

Example 2201-(2,4-Difluorophenyl)-7-[3-hydroxypyrrolidin-1-yl]-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.53 (d, 1H), 8.61 (s, 1H), 8.28 (d,1H), 7.86-7.76 (m, 1H), 7.61-7.53 (m, 1H), 7.36-7.28 (m, 1H), 6.80-6.71(m, 1H), 5.08-4.87 (m, 1H), 4.80-4.67 (m, 1H), 4.43.4.22 (m, 1H),3.58-3.00 (m, 4H), 2.08-1.57 (m, 4H), 0.97 (t, 3H).

LC-MS (Method 1): R_(t)=1.05 min; 497 [M+H]⁺.

Example 2211-(2,4-Difluorophenyl)-4-oxo-7-[4-oxohexahydrpyrrolo[3,4-c]pyrrol-2(1H)-yl]-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

To a solution of 242 mg (381 μmol) of the diastereomer mixture fromExample 83A in 3 ml of THF were added, at 0° C., 476 μl (1.90 mmol) ofhydrochloric acid (4M in dioxane). The mixture was stirred at 0° C. for30 min and at RT overnight. The solvent was removed under reducedpressure and the residue was purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90%acetonitrile and a further 3 min. 90% acetonitrile), and 168 mg (83% oftheory, 100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.48 (d, 1H), 8.62 (s, 1H), 8.31 (d,1H), 7.87-7.70 (m, 2H), 7.63-7.52 (m, 1H), 7.37-7.27 (m, 1H), 6.87-6.70(br. s, 1H), 4.80-4.66 (m, 1H), 3.92-2.88 (br. m, 8H), 1.94-1.81 (m,1H), 1.70-1.56 (m, 1H), 0.97 (t, 3H).

LC-MS (Method 3): R_(t)=1.74 min; 536 [M+H]⁺.

167 mg of the title compound (diastereomer mixture) were separated intothe diastereomers by chiral HPLC (preparative HPLC: column: ChiralpakAD-H 5 μm 250×20 mm; eluent: 30% isopropanol, 70% isohexane;temperature: 25° C.; flow rate: 20 ml/min; UV detection: 230 nm).

This gave (in the sequence of elution from the column) 63.6 mg ofdiastereomer 1 (99% de) R_(t)=3.46 min and 67.9 mg (99% de) ofdiastereomer 2 R_(t)=6.09 min.

[Analytical HPLC: column: Daicel AD-3 3 μm 30×4.6 mm; eluent: 70%isopropanol, 50% isohexane; UV detection: 220 nm].

Diastereomer 1 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90%acetonitrile and a further 3 min. 90% acetonitrile)), and 41 mg (20% oftheory, 100% purity) of the title compound from Example 222 wereobtained.

Diastereomer 2 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90%acetonitrile and a further 3 min. 90% acetonitrile)), and 38 mg (18% oftheory, 100% purity) of the title compound from Example 223 wereobtained.

Example 2221-(2,4-Difluorophenyl)-4-oxo-7-[4-oxohexahydrpyrrolo[3,4-c]pyrrol-2(1H)-yl]-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.48 (d, 1H), 8.62 (s, 1H), 8.31 (d,1H), 7.86-7.73 (m, 2H), 7.63-7.53 (m, 1H), 7.37-7.28 (m, 1H), 6.87-6.71(br. s, 1H), 4.80-4.68 (m, 1H), 3.93-2.89 (br. m, 8H), 1.94-1.81 (m,1H), 1.70-1.57 (m, 1H), 0.97 (t, 3H).

LC-MS (Method 1): R_(t)=0.97 min; 536 [M+H]⁺.

Example 2231-(2,4-Difluorophenyl)-4-oxo-7-[4-oxohexahydrpyrrolo[3,4-c]pyrrol-2(1H)-yl]-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.48 (d, 1H), 8.62 (s, 1H), 8.31 (d,1H), 7.86-7.73 (m, 2H), 7.63-7.54 (m, 1H), 7.37-7.28 (m, 1H), 6.87-6.70(br. s, 1H), 4.81-4.67 (m, 1H), 3.93-2.89 (br. m, 8H), 1.94-1.82 (m,1H), 1.70-1.57 (m, 1H), 0.97 (t, 3H).

LC-MS (Method 1): R_(t)=0.97 min; 536 [M+H]⁺.

Example 2241-(2,4-Difluorophenyl)-7-[3-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP2, 150 mg (326 μmol) of the compound from Example 67A(97% purity) were reacted with 33.0 mg (326 μmol) ofrac-3-hydroxy-2-pyrrolidin-2-one in the presence of 67.7 mg (490 μmol)of potassium carbonate, 7.3 mg (33 μmol) of palladium(II) acetate and 38mg (65 μmol) of Xantphos in 3 ml of dioxane. The reaction mixture wasfiltered, washed through with acetonitrile and concentrated, and theresidue was purified by means of flash chromatography (cyclohexane/ethylacetate gradient). 92.5 mg (55% of theory, 99% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.21 (d, 1H), 8.86 (s, 1H), 8.73 (d,1H), 8.56-8.49 (m, 1H), 7.92-7.82 (m, 1H), 7.67-7.56 (m, 1H), 7.40-7.31(m, 1H), 5.90 (d, 1H), 4.84-4.70 (m, 1H), 4.44-4.32 (m, 1H), 3.63-3.49(m, 1H), 3.37-3.23 (m, 1H), 2.37-2.26 (m, 1H), 1.96-1.59 (m, 3H), 0.98(t, 3H).

LC-MS (Method 3): R_(t)=1.88 min; 511 [M+H]⁺.

90 mg of the title compound (diastereomer mixture) were separated intothe diastereomers by chiral HPLC (preparative HPLC: column: ChiralcelOX-H 5 μm 250×20 mm; eluent: 40% ethanol, 60% isohexane; temperature:30° C.; flow rate: 15 ml/min; UV detection: 220 nm).

This gave (in the sequence of elution from the column) 43 mg ofdiastereomer 1 (99% de) R_(t)=8.76 min and 46 mg (99% de) ofdiastereomer 2 R_(t)=10.65 min.

[Analytical HPLC: column: Chiralcel OX-H 5 μm 250×4.6 mm; eluent: 40%ethanol, 60% isohexane; temperature: 30° C.; flow rate: 1 ml/min; UVdetection: 220 nm]

Diastereomer 1 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90%acetonitrile and a further 3 min. 90% acetonitrile)), and 36.6 mg (22%of theory, 100% purity) of the title compound from Example 225 wereobtained.

Diastereomer 2 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90%acetonitrile and a further 3 min. 90% acetonitrile)), and 36.7 mg (22%of theory, 100% purity) of the title compound from Example 226 wereobtained.

Example 2251-(2,4-Difluorophenyl)-7-[3-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.21 (d, 1H), 8.86 (s, 1H), 8.73 (d,1H), 8.56-8.50 (m, 1H), 7.92-7.82 (m, 1H), 7.66-7.57 (m, 1H), 7.40-7.32(m, 1H), 5.90 (d, 1H), 4.84-4.70 (m, 1H), 4.44-4.33 (m, 1H), 3.63-3.51(m, 1H), 3.38-3.25 (m, 1H), 2.38-2.26 (m, 1H), 1.96-1.60 (m, 3H), 0.98(t, 3H).

LC-MS (Method 3): R_(t)=1.86 min; 511 [M+H]⁺.

Example 2261-(2,4-Difluorophenyl)-7-[3-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.21 (d, 1H), 8.86 (s, 1H), 8.73 (d,1H), 8.56-8.49 (m, 1H), 7.91-7.83 (m, 1H), 7.66-7.57 (m, 1H), 7.39-7.33(m, 1H), 5.90 (d, 1H), 4.83-4.70 (m, 1H), 4.44-4.33 (m, 1H), 3.63-3.50(m, 1H), 3.38-3.24 (m, 1H), 2.37-2.26 (m, 1H), 1.96-1.60 (m, 3H), 0.98(t, 3H).

LC-MS (Method 3): R_(t)=1.87 min; 511 [M+H]⁺.

Example 2271-(2,4-Difluorophenyl)-7-[(3S)-3-fluoropyrrolidin-1-yl]-4-oxo-N-[1-(trifluoromethoxy)propan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP3, 150 mg (325 μmol) of the compound from Example 74Awere reacted with 48.9 g (390 μmol) of (S)-3-fluoropyrrolidinehydrochloride and 0.20 ml (1.1 mmol) of N,N-diisopropylethylamine in1.45 ml of dimethylformamide. The crude product was diluted withacetonitrile and purified by means of preparative HPLC (column:Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05% formicacid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90% acetonitrileand a further 3 min. 90% acetonitrile), and 141 mg (84% of theory, 99%purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.15 (d, 1H), 8.57 (s, 1H), 8.32 (d,1H), 7.85-7.74 (m, 1H), 7.64-7.51 (m, 1H), 7.37-7.27 (m, 1H), 6.84-6.74(m, 1H), 5.56-5.22 (m, 1H), 4.39-4.28 (m, 1H), 4.21-4.11 (m, 2H),3.88-3.03 (m, 4H), 2.38-1.92 (m, 2H), 1.25 (d, 3H).

LC-MS (Method 3): R_(t)=2.13 min; 515 [M+H]⁺.

135 mg of the title compound (diastereomer mixture) were separated intothe diastereomers by chiral HPLC (preparative HPLC: column: OZ-H 5 μm250×20 mm; eluent: 50% ethanol (with 2% diethylamine), 50% isohexane;temperature: 25° C.; flow rate: 15 ml/min; UV detection: 210 nm).

This gave (in the sequence of elution from the column) 50 mg ofdiastereomer 1 (99% de) R_(t)=1.02 min and 57 mg (92.3% de) ofdiastereomer 2 R_(t)=1.33 min.

[Analytical HPLC: column: Chiralpak OZ-3 3 μm 50×4.6 mm; eluent: 50%ethanol (with 2% diethylamine), 50% isohexane; flow rate: 1 ml/min; UVdetection: 220 nm]

Diastereomer 1 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90%acetonitrile and a further 3 min. 90% acetonitrile)), and 40.5 mg (24%of theory, 99% purity) of the title compound from Example 228 wereobtained.

Diastereomer 2 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90%acetonitrile and a further 3 min. 90% acetonitrile)), and 46.7 mg (28%of theory, 99% purity) of the title compound from Example 229 wereobtained.

Example 2281-(2,4-Difluorophenyl)-7-[(3S)-3-fluoropyrrolidin-1-yl]-4-oxo-N-[1-(trifluoromethoxy)propan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.15 (d, 1H), 8.57 (s, 1H), 8.32 (d,1H), 7.84-7.76 (m, 1H), 7.63-7.52 (m, 1H), 7.37-7.28 (m, 1H), 6.83-6.75(m, 1H), 5.55-5.24 (m, 1H), 4.39-4.29 (m, 1H), 4.20-4.12 (m, 2H),3.82-3.05 (m, 4H), 2.35-1.99 (m, 2H), 1.25 (d, 3H).

LC-MS (Method 3): R_(t)=2.09 min; 515 [M+H]⁺.

Example 2291-(2,4-Difluorophenyl)-7-[(3S)-3-fluoropyrrolidin-1-yl]-4-oxo-N-[1-(trifluoromethoxy)propan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.15 (d, 1H), 8.57 (s, 1H), 8.32 (d,1H), 7.84-7.75 (m, 1H), 7.64-7.53 (m, 1H), 7.37-7.27 (m, 1H), 6.84-6.74(m, 1H), 5.57-5.22 (m, 1H), 4.39-4.29 (m, 1H), 4.21-4.12 (m, 2H),3.83-3.03 (m, 4H), 2.36-1.92 (m, 2H), 1.25 (d, 3H).

LC-MS (Method 3): R_(t)=2.08 min; 515 [M+H]⁺.

Example 230rac-1-(2,4-Difluorophenyl)-4-oxo-7-(2-oxopyrrolidin-1-yl)-N-[1-(trifluoromethoxy)propan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 150 mg (325 μmol) of the compound from Example 74Awere reacted with 27.6 mg (325 μmol) of pyrrolidin-2-one in the presenceof 67.3 mg (487 μmol) of potassium carbonate, 13 mg (58 μmol) ofpalladium(II) acetate and 34 mg (58 μmol) of Xantphos in 4 ml ofdioxane. The crude product was dissolved in 3 ml of acetonitrile and 0.5ml of water and purified by means of preparative HPLC (column:Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05% formicacid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90% acetonitrileand a further 3 min. 90% acetonitrile), and 3.3 mg (2% of theory, 99%purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=9.92 (d, 1H), 8.78 (s, 1H), 8.69 (d,1H), 8.49 (d, 1H), 7.89-7.91 (m, 1H), 7.65-7.58 (m, 1H), 7.39-7.33 (m,1H), 4.41-4.32 (m, 1H), 4.22-4.14 (m, 2H), 3.61-3.50 (m, 2H), 2.00-1.91(m, 2H), 1.26 (d, 3H).

LC-MS (Method 3): R_(t)=2.04 min; 511 [M+H]⁺.

Example 2311-(2,4-Difluorophenyl)-7-(dimethylamino)-4-oxo-N-[1-(trifluoromethoxy)propan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 100 mg (290 μmol) of the compound from Example 36Awere reacted with 78.0 mg (434 μmol) of(+)-1-(trifluoromethoxy)propan-2-amine hydrochloride (optical rotation:+10°, c=0.4000 g/100 ml, MeOH, 20° C.) in the presence of 110 mg (290μmol) of HATU and 151 μl (869 μmol) of N,N-diisopropylethylamine in 3 mlof dimethylformamide. 1 ml of aqueous 1M hydrochloric acid and 10 ml ofwater were added, and the precipitate was filtered off with suction anddried under high vacuum overnight. The crude product was purified bymeans of flash chromatography (cyclohexane/ethyl acetate gradient), and80 mg (58% of theory; 99% purity) of the title compound (non-racemicmixture) were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.15 (d, 1H), 8.55 (s, 1H), 8.28 (d,1H), 7.83-7.75 (m, 1H), 7.61-7.54 (m, 1H), 7.35-7.29 (m, 1H), 6.92 (d,1H), 4.39-4.29 (m, 1H), 4.20-4.12 (m, 2H), 2.94 (br. s, 6H); 1.25 (d,3H).

LC-MS (Method 1): R_(t)=1.12 min; 471 [M+H]⁺.

Example 2321-(2,4-Difluorophenyl)-4-oxo-7-(pyrrolidin-1-yl)-N-[1-(trifluoromethoxy)propan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 100 mg of the compound from Example 57A were reactedwith 72.5 mg (404 μmol) of (+)-1-(trifluoromethoxy)propan-2-aminehydrochloride (optical rotation: +10°, c=0.4000 g/100 ml, MeOH, 20° C.)in the presence of 102 mg (269 μmol) of HATU and 141 μl (808 μmol) ofN,N-diisopropylethylamine in 3 ml of dimethylformamide. 1 ml of aqueous1M hydrochloric acid and 10 ml of water were added, and the precipitatewas filtered off with suction and dried under high vacuum overnight. Thecrude product was purified by means of flash chromatography(cyclohexane/ethyl acetate gradient), and 97 mg (72% of theory; 99%purity) of the title compound (non-racemic mixture) were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.17 (d, 1H), 8.54 (s, 1H), 8.27 (d,1H), 7.82-7.74 (m, 1H), 7.60-7.53 (m, 1H), 7.34-7.28 (m, 1H), 6.73 (d,1H), 4.39-4.29 (m, 1H), 4.21-4.12 (m, 2H), 3.50-3.35 (br. s, 2H),3.23-3.02 (br. s, 2H), 2.01-1.73 (m, 4H), 1.25 (d, 3H).

LC-MS (Method 1): R_(t)=1.21 min; 497 [M+H]⁺.

Example 2331-(2,4-Difluorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[1-phenyl-2-(trifluoromethoxy)ethyl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 200 mg (363 μmol) of the compound from Example 75A(95% purity) were reacted with 36.7 mg (363 μmol) of(S)-(−)-4-hydroxy-2-pyrrolidinone in the presence of 75.2 mg (544 μmol)of potassium carbonate, 8.1 mg (36 μmol) of palladium(II) acetate and 42mg (73 μmol) of Xantphos in 3.6 ml of dioxane. The crude product waspurified twice by means of preparative HPLC (column: Chromatorex C18, 10μm, 125×30 mm, solvent: acetonitrile/0.05% formic acid gradient; (0 to 3min. 10% acetonitrile to 35 min. 90% acetonitrile and a further 3 min.90% acetonitrile)), and 37.8 mg (18% of theory, 100% purity) of thetitle compound (non-racemic mixture) were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.60 (d, 1H), 8.80 (s, 1H), 8.74 (d,1H), 8.55-8.48 (m, 1H), 7.90-7.81 (m, 1H), 7.66-7.58 (m, 1H), 7.51-7.29(m, 6H), 5.55-5.48 (m, 1H), 5.32 (dd, 1H), 4.53-4.40 (m, 2H), 4.31-4.25(m, 1H), 3.72-3.61 (m, 1H), 3.52-3.42 (m, 1H), 3.00-2.88 (m, 1H),2.42-2.29 (m, 1H).

LC-MS (Method 3): R_(t)=1.94 min; 589 [M+H]⁺.

Example 2341-(2,4-Difluorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[1-(trifluoromethoxy)butan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP2, 100 mg (210 μmol) of the compound from Example 76Awere reacted with 21.2 mg (210 μmol) of(S)-(−)-4-hydroxy-2-pyrrolidinone in the presence of 103 mg (315 μmol)of caesium carbonate, 8.5 mg (38 μmol) of palladium(II) acetate and 18mg (31 μmol) of Xantphos in 2.1 ml of dioxane. The crude product waspurified by means of flash chromatography (cyclohexane/ethyl acetategradient) and preparative thin-layer chromatography (1 mm silica plates,20×20 cm, cyclohexane/ethyl acetate=35/65). The product fraction wasvisualized by UV detection and scratched off, and eluted from the silicagel with ethyl acetate. The mixture was filtered through Celite and thesolvent was removed under reduced pressure. The residue was lyophilizedfrom water/acetonitrile, and 17 mg (15% of theory; 100% purity) of thetitle compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=9.90 (d, 1H), 8.79 (s, 1H), 8.70 (d,1H), 8.53-8.47 (m, 1H), 7.92-7.81 (m, 1H), 7.67-7.58 (m, 1H), 7.41-7.33(m, 1H), 5.32 (dd, 1H), 4.31-4.13 (m, 4H), 3.72-3.62 (m, 1H), 3.52-3.43(m, 1H), 3.00-2.88 (m, 1H), 2.41-2.32 (m, 1H), 1.76-1.53 (m, 2H), 0.95(t, 3H).

LC-MS (Method 1): R_(t)=0.99 min; 541 [M+H]⁺.

Example 2351-(2,4-Difluorophenyl)-N-[1-(2-fluorophenyl)ethyl]-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP2, 97.0 mg (212 μmol) of the compound from Example 77Awere reacted with 21.4 mg (212 μmol) of(S)-(−)-4-hydroxy-2-pyrrolidinone in the presence of 104 mg (318 μmol)of caesium carbonate, 8.6 mg (38 μmol) of palladium(II) acetate and 18mg (31 μmol) of Xantphos in 2 ml of dioxane. The crude product waspurified by means of flash chromatography (cyclohexane/ethyl acetategradient) and lyophilized from acetonitrile/water. 45.8 mg (41% oftheory, 100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.33 (d, 1H), 8.74 (s, 1H), 8.71 (d,1H), 8.54-8.48 (m, 1H), 7.90-7.78 (m, 1H), 7.66-7.57 (m, 1H), 7.48-7.42(m, 1H), 7.41-7.29 (m, 2H), 7.24-7.16 (m, 2H), 5.44-5.26 (m, 2H),4.31-4.24 (m, 1H), 3.72-3.60 (m, 1H), 3.52-3.42 (m, 1H), 2.99-2.87 (m,1H), 2.42-2.31 (m, 1H), 1.52 (d, 3H).

LC-MS (Method 1): R_(t)=0.97 min; 523 [M+H]⁺.

Example 2361-(2,4-Difluorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[1,1,1-trifluoro-3-methoxy-2-methylpropan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP2, 110 mg (231 μmol) of the compound from Example 78Awere reacted with 23.3 mg (231 μmol) of(S)-(−)-4-hydroxy-2-pyrrolidinone in the presence of 96.9 mg (297 μmol)of caesium carbonate, 8.0 mg (36 μmol) of palladium(II) acetate and 18mg (31 μmol) of Xantphos in 2.3 ml of dioxane. The crude product waspurified by means of flash chromatography (cyclohexane/ethyl acetategradient) and preparative thin-layer chromatography (1 mm silica plates,20×20 cm, dichloromethane/methanol=95/5). The product fraction wasvisualized by UV detection and scratched off, and eluted from the silicagel with ethyl acetate. The mixture was filtered through Celite and thesolvent was removed under reduced pressure. The residue was lyophilizedfrom water/acetonitrile, and 49 mg (39% of theory; 100% purity) of thetitle compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.50 (br. s, 1H), 8.79 (s, 1H), 8.71(d, 1H), 8.54-8.48 (m, 1H), 7.91-7.81 (m, 1H), 7.67-7.59 (m, 1H),7.41-7.33 (m, 1H), 5.32 (dd, 1H), 4.31-4.26 (m, 1H), 3.91-3.84 (m, 1H),3.77-3.61 (m, 2H), 3.52-3.42 (m, 1H), 3.36 (s, 3H), 2.99-2.88 (m, 1H),2.41-2.31 (m, 1H), 1.64 (s, 3H).

LC-MS (Method 1): R_(t)=0.96 min; 541 [M+H]⁺.

Example 2371-(2,4-Difluorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[4-(trifluoromethyl)tetrahydro-2H-pyran-4-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 106 mg (217 μmol) of the compound from Example 79Awere reacted with 21.9 mg (217 μmol) of(S)-(−)-4-hydroxy-2-pyrrolidinone in the presence of 106 mg (326 μmol)of caesium carbonate, 8.8 mg (39 μmol) of palladium(II) acetate and 23mg (39 μmol) of Xantphos in 2.3 ml of dioxane. The crude product waspurified by means of flash chromatography (cyclohexane/ethyl acetategradient) and twice by means of preparative thin-layer chromatography (1mm silica plates, 20×20 cm, cyclohexane/ethyl acetate=1/1, thendichloromethane/methanol=90/10). The product fraction was visualized byUV detection and scratched off, and eluted from the silica gel withethyl acetate or dichloromethane. The mixture was filtered through afine filter and the solvent was removed under reduced pressure. Theresidue was lyophilized from water/acetonitrile, and 42.8 mg (35% oftheory; 99% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.34 (s, 1H), 8.82 (s, 1H), 8.72 (d,1H), 8.55-8.50 (m, 1H), 7.92-7.83 (m, 1H), 7.67-7.59 (m, 1H), 7.41-7.33(m, 1H), 5.32 (dd, 1H), 4.31-4.25 (m, 1H), 3.94-3.85 (m, 2H), 3.72-3.62(m, 1H), 3.58-3.42 (m, 3H), 3.00-2.89 (m, 1H), 2.45-2.31 (m, 2H),1.95-1.83 (m, 2H).

LC-MS (Method 4): R_(t)=2.83 min; 553 [M+H]⁺.

Example 2381-(2,4-Difluorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[3-(trifluoromethyl)tetrahydrofuran-3-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP1, 82 mg (0.13 mmol, 65% purity) of the compound fromExample 63A were reacted with 30.9 mg (199 μmol) ofrac-3-(trifluoromethyl)tetrahydrofuran-3-amine in the presence of 50.5mg (133 μmol) of HATU and 32.0 μl (186 μmol) ofN,N-diisopropylethylamine in 1.3 ml of dimethylformamide. The crudeproduct was purified by means of flash chromatography (cyclohexane/ethylacetate gradient), and 39.8 mg (56% of theory; 100% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.62 (s, 1H), 8.83 (s, 1H), 8.71 (d,1H), 8.55-8.50 (m, 1H), 7.91-7.81 (m, 1H), 7.67-7.59 (m, 1H), 7.41-7.33(m, 1H), 5.32 (dd, 1H), 4.34-4.25 (m, 2H), 4.16-4.09 (m, 1H), 4.01-3.93(m, 1H), 3.92-3.83 (m, 1H), 3.71-3.61 (m, 1H), 3.52-3.41 (m, 1H),3.00-2.88 (m, 1H), 2.41-2.31 (m, 1H).

LC-MS (Method 1): R_(t)=0.90 min; 539 [M+H]⁺.

Example 2391-(2-Fluorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 130 mg (304 μmol) of the compound from Example 82Awere reacted with 30.7 mg (304 μmol) of(S)-(−)-4-hydroxy-2-pyrrolidinone in the presence of 149 mg (456 μmol)of caesium carbonate, 12 mg (55 μmol) of palladium(II) acetate and 63.3mg (109 μmol) of Xantphos in 6 ml of dioxane. The crude product wasdiluted with 3 ml of acetonitrile and 0.5 ml of water and purified bymeans of preparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm,solvent: acetonitrile/0.05% formic acid gradient; (0 to 3 min. 10%acetonitrile to 35 min. 90% acetonitrile and a further 3 min. 90%acetonitrile), and 51.3 mg (35% of theory, 99% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.23 (d, 1H), 8.82 (s, 1H), 8.72 (d,1H), 8.55-8.49 (m, 1H), 7.82-7.76 (m, 1H), 7.72-7.65 (m, 1H), 7.57-7.43(m, 2H), 5.32 (dd, 1H), 4.84-4.70 (m, 1H), 4.29-4.22 (m, 1H), 3.69-3.57(m, 1H), 3.50-3.39 (m, 1H), 2.99-2.87 (m, 1H), 2.41-2.30 (m, 1H),1.96-1.84 (m, 1H), 1.73-1.59 (m, 1H), 0.98 (t, 3H).

LC-MS (Method 1): R_(t)=0.96 min; 493 [M+H]⁺.

Example 2401-(2-Chlorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Atropisomer Mixture)

According to GP1, 30 mg (75 μmol) of the compound from Example 64A werereacted with 18.4 mg (113 μmol) of (R)-1,1,1-trifluoro-2-butylaminehydrochloride in the presence of 29 mg (75 μmol) of HATU and 39 μl (0.23mmol) of N,N-diisopropylethylamine in 0.8 ml of dimethylformamide. Themixture was diluted with 1 ml of acetonitrile and 0.5 ml of water andthe solution was purified by means of preparative HPLC (column:Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05% formicacid gradient; 0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrileand for a further 3 min 90% acetonitrile). 23 mg (60% of theory, 99%purity) of the title compound were obtained (as an atropisomer mixture).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.25 (d, 1H), 8.75 (d, 1H), 8.72 (d,1H), 8.51 (dd, 1H), 7.84-7.76 (m, 2H), 7.70-7.59 (m, 2H), 5.31 (dd, 1H),4.84-4.70 (m, 1H), 4.27-4.20 (m, 1H), 3.61-3.52 (m, 1H), 3.41-3.34 (m,1H), 2.97-2.87 (m, 1H), 2.40-2.30 (m, 1H), 1.96-1.84 (m, 1H), 1.75-1.60(m, 1H), 1.02-0.95 (m, 3H).

LC-MS (Method 1): R_(t)=1.00 min; 509 [M+H]⁺.

Example 2411-(2,4-Difluorophenyl)-N-[1-(2,6-difluorophenyl)-2,2,2-trifluoroethyl]-7-[(3S)-3-fluoropyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP3, 150 mg (283 μmol) of the compound from Example 80Awere reacted with 43 mg (0.28 mmol) of (S)-3-fluoropyrrolidinehydrochloride and 0.17 ml (0.99 mmol) of N,N-diisopropylethylamine in1.3 ml of dimethylformamide. The crude product was purified by means ofpreparative HPLC (column: Chromatorex C18, 10 μm, 125×40 mm, solvent:acetonitrile/0.05% formic acid gradient; (0 to 3 min. 10% acetonitrileto 40 min. 90% acetonitrile and a further 3 min. 90% acetonitrile), and119 mg (72% of theory, 100% purity) of the title compound were obtained.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=11.61 (d, 1H), 8.65 (s, 1H), 8.36 (d,1H), 7.89-7.69 (m, 1H), 7.67-7.51 (m, 2H), 7.38-7.25 (m, 3H), 6.82 (br.d, 1H), 6.49-6.38 (m, 1H), 5.57-5.23 (m, 1H), 3.86-3.44 (m, 3H),3.25-3.01 (m, 1H), 2.32-2.08 (m, 2H).

LC-MS (Method 1): R_(t)=1.31 min; 583 [M+H]⁺.

131 mg of the title compound (diastereomer mixture) were separated intothe diastereomers by chiral HPLC (preparative HPLC: column: DaicelChiralpak IC 5 μm 250×20 mm; eluent: 50% isohexane, 50% ethanol+0.2%diethylamine; temperature: 40° C.; flow rate: 20 ml/min; UV detection:220 nm).

This gave (in the sequence of elution from the column) 57 mg ofdiastereomer 1 (99% de) R_(t)=4.13 min and 58 mg (99% de) ofdiastereomer 2 R_(t)=5.55 min.

[Analytical HPLC: column: Daicel Chiralpak IC 5 m 250×4.6 mm; eluent:50% isohexane, 50% ethanol+0.2% diethylamine; temperature: 40° C.; flowrate: 1 ml/min; UV detection: 235 nm]

Example 2421-(2,4-Difluorophenyl)-N-[1-(2,6-difluorophenyl)-2,2,2-trifluoroethyl]-7-[(3S)-3-fluoropyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=11.61 (d, 1H), 8.65 (s, 1H), 8.36 (d,1H), 7.89-7.69 (m, 1H), 7.68-7.51 (m, 2H), 7.37-7.23 (m, 3H), 6.88-6.73(m, 1H), 6.50-6.34 (m, 1H), 5.57-5.21 (m, 1H), 3.87-3.34 (m, 3H),3.22-3.01 (m, 1H), 2.34-1.94 (m, 2H).

LC-MS (Method 3): R_(t)=2.36 min; 583 [M+H]⁺.

Example 2431-(2,4-Difluorophenyl)-N-[1-(2,6-difluorophenyl)-2,2,2-trifluoroethyl]-7-[(3S)-3-fluoropyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2)

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=11.61 (d, 1H), 8.65 (s, 1H), 8.36 (d,1H), 7.90-7.69 (m, 1H), 7.67-7.49 (m, 2H), 7.38-7.26 (m, 3H), 6.82 (br.d, 1H), 6.49-6.37 (m, 1H), 5.58-5.21 (m, 1H), 3.86-3.34 (m, 3H),3.24-3.00 (m, 1H), 2.34-1.97 (m, 2H).

LC-MS (Method 3): R_(t)=2.34 min; 583 [M+H]⁺.

Example 2441-(2,4-Difluorophenyl)-N-[1-(2,6-difluorophenyl)-2,2,2-trifluoroethyl]-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP2, 200 mg (377 μmol) of the compound from Example 80Awere reacted with 45.8 mg (453 μmol) of (4S)-4-hydroxypyrrolidin-2-onein the presence of 78.3 mg (566 μmol) of potassium carbonate, 17 mg (75μmol) of palladium(II) acetate and 44 mg (75 μmol) of Xantphos in 3.4 mlof dioxane. The crude product was purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×40 mm, solvent: acetonitrile/0.1%formic acid gradient; (0 to 3 min. 10% acetonitrile to 40 min. 90%acetonitrile and a further 3 min. 90% acetonitrile), and 168 mg (75% oftheory, 100% purity) of the title compound were obtained.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=11.37 (d, 1H), 8.87 (s, 1H), 8.75 (d,1H), 8.52 (dd, 1H), 7.94-7.75 (m, 1H), 7.68-7.57 (m, 2H), 7.42-7.26 (m,3H), 6.50-6.39 (m, 1H), 5.37-5.26 (m, 1H), 4.28 (br. d, 1H), 3.73-3.60(m, 1H), 3.53-3.40 (m, 1H), 3.01-2.87 (m, 1H), 2.42-2.31 (m, 1H).

LC-MS (Method 3): R_(t)=2.01 min; 595 [M+H]⁺.

133 mg of the title compound (diastereomer mixture) were separated intothe diastereomers by chiral HPLC (preparative HPLC: column: DaicelChiralpak ID 5 μm 250×20 mm; eluent: 80% isohexane, 20% ethanol;temperature: 23° C.; flow rate: 30 ml/min; UV detection: 220 nm).

This gave (in the sequence of elution from the column) 53.9 mg ofdiastereomer 1 (99% de) R_(t)=2.12 min and 52.2 mg (99% de) ofdiastereomer 2 R_(t)=3.03 min.

[Analytical HPLC: column: Daicel Chiralpak ID-3 3 m 50×4.6 mm; eluent:80% isohexane, 20% ethanol; temperature: 30° C.; flow rate: 1 ml/min; UVdetection: 220 nm]

Example 2451-(2,4-Difluorophenyl)-N-[1-(2,6-difluorophenyl)-2,2,2-trifluoroethyl]-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=11.37 (d, 1H), 8.88 (s, 1H), 8.75 (d,1H), 8.52 (dd, 1H), 7.92-7.76 (m, 1H), 7.68-7.57 (m, 2H), 7.41-7.25 (m,3H), 6.50-6.39 (m, 1H), 5.32 (dd, 1H), 4.28 (br. d, 1H), 3.72-3.60 (m,1H), 3.46 (t, 1H), 3.00-2.87 (m, 1H), 2.37 (dd, 1H).

LC-MS (Method 3): R_(t)=2.01 min; 595 [M+H]⁺.

Example 2461-(2,4-Difluorophenyl)-N-[1-(2,6-difluorophenyl)-2,2,2-trifluoroethyl]-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2)

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=11.37 (dd, 1H), 8.87 (s, 1H), 8.75 (d,1H), 8.52 (dd, 1H), 7.95-7.75 (m, 1H), 7.68-7.57 (m, 2H), 7.41-7.26 (m,3H), 6.50-6.38 (m, 1H), 5.32 (dd, 1H), 4.31-4.25 (br. d, 1H), 3.71-3.60(m, 1H), 3.52-3.41 (m, 1H), 3.00-2.88 (m, 1H), 2.37 (dd, 1H).

LC-MS (Method 3): R_(t)=2.00 min; 595 [M+H]⁺.

Example 2471-(2,4-Difluorophenyl)-N-[1-(2,6-difluorophenyl)-2,2,2-trifluoroethyl]-7-[3-hydroxy-2-oxopiperidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP2, 150 mg (283 μmol) of the compound from Example 80Awere reacted with 39.1 mg (340 μmol) of rac-3-hydroxypiperidin-2-one inthe presence of 58.7 mg (425 μmol) of potassium carbonate, 13 mg (57μmol) of palladium(II) acetate and 33 mg (57 μmol) of Xantphos in 2.5 mlof dioxane. The crude product was purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×40 mm, solvent: acetonitrile/0.1%formic acid gradient; (0 to 3 min. 10% acetonitrile to 40 min. 90%acetonitrile and a further 3 min. 90% acetonitrile), and 102 mg (59% oftheory, 100% purity) of the title compound were obtained.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=11.34 (br. d, 1H), 8.89 (s, 1H), 8.70(d, 1H), 8.17-8.09 (m, 1H), 7.94-7.75 (m, 1H), 7.68-7.56 (m, 2H),7.41-7.27 (m, 3H), 6.51-6.39 (m, 1H), 5.52-5.46 (m, 1H), 4.27-4.17 (m,1H), 3.71-3.58 (m, 1H), 3.54-3.40 (m, 1H), 2.12-2.01 (m, 1H), 1.86-1.71(m, 1H), 1.71-1.57 (m, 1H).

LC-MS (Method 3): R_(t)=2.11 min; 609 [M+H]⁺.

91.2 mg of the title compound (racemic diastereomer mixture) wereseparated into the enantiomeric diastereomers by chiral HPLC(preparative HPLC: column: Daicel Chiralpak AZ-H 5 m 250×30 mm; eluent:50% isohexane, 20% ethanol; temperature: 25° C.; flow rate: 50 ml/min;UV detection: 220 nm).

This gave (in the sequence of elution from the column) 17.8 mg ofdiastereomer 1 (96.5% de) R_(t)=3.19 min, 14.5 mg (95% de) ofdiastereomer 2 R_(t)=4.21 min, 17.4 mg (97% de) of diastereomer 3R_(t)=6.11 min, and 14.5 mg (97% de) of diastereomer 4 R_(t)=10.80 min.

[Analytical HPLC: column: Daicel AZ-3 3 m 50×4.6 mm; eluent: 50%isohexane, 50% ethanol; temperature: 30° C.; flow rate: 1 ml/min; UVdetection: 220 nm]

Example 2481-(2,4-Difluorophenyl)-N-[1-(2,6-difluorophenyl)-2,2,2-trifluoroethyl]-7-[3-hydroxy-2-oxopiperidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=11.34 (br. d, 1H), 8.89 (s, 1H), 8.70(d, 1H), 8.17-8.10 (m, 1H), 7.93-7.76 (m, 1H), 7.68-7.57 (m, 2H),7.40-7.27 (m, 3H), 6.51-6.39 (m, 1H), 5.52-5.46 (m, 1H), 4.27-4.18 (m,1H), 3.71-3.59 (m, 1H), 3.54-3.41 (m, 1H), 2.12-2.01 (m, 1H), 1.83-1.73(m, 2H), 1.71-1.58 (m, 1H).

LC-MS (Method 3): R_(t)=2.12 min; 609 [M+H]⁺.

Example 2491-(2,4-Difluorophenyl)-N-[1-(2,6-difluorophenyl)-2,2,2-trifluoroethyl]-7-[3-hydroxy-2-oxopiperidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2)

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=11.37-11.31 (m, 1H), 8.89 (s, 1H),8.70 (d, 1H), 8.13 (dd, 1H), 7.94-7.75 (m, 1H), 7.68-7.56 (m, 2H),7.41-7.26 (m, 3H), 6.51-6.38 (m, 1H), 5.52-5.46 (m, 1H), 4.27-4.16 (m,1H), 3.72-3.58 (m, 1H), 3.53-3.39 (m, 1H), 2.12-2.01 (m, 1H), 1.83-1.73(m, 2H), 1.72-1.57 (m, 1H).

LC-MS (Method 3): R_(t)=2.13 min; 609 [M+H]⁺.

Example 2501-(2,4-Difluorophenyl)-N-[1-(2,6-difluorophenyl)-2,2,2-trifluoroethyl]-7-[3-hydroxy-2-oxopiperidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(3rd diastereomer)

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=11.37-11.31 (m, 1H), 8.89 (s, 1H),8.70 (d, 1H), 8.13 (dd, 1H), 7.94-7.75 (m, 1H), 7.68-7.56 (m, 2H),7.40-7.26 (m, 3H), 6.51-6.39 (m, 1H), 5.52-5.46 (m, 1H), 4.26-4.17 (m,1H), 3.72-3.59 (m, 1H), 3.52-3.40 (m, 1H), 2.12-2.01 (m, 1H), 1.84-1.73(m, 2H), 1.72-1.58 (m, 1H).

LC-MS (Method 3): R_(t)=2.12 min; 609 [M+H]⁺.

Example 2511-(2,4-Difluorophenyl)-N-[1-(2,6-difluorophenyl)-2,2,2-trifluoroethyl]-7-[3-hydroxy-2-oxopiperidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(4th diastereomer)

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=11.34 (br. d, 1H), 8.89 (s, 1H), 8.70(d, 1H), 8.17-8.09 (m, 1H), 7.93-7.76 (m, 1H), 7.68-7.57 (m, 2H),7.40-7.28 (m, 3H), 6.51-6.39 (m, 1H), 5.52-5.46 (m, 1H), 4.27-4.18 (m,1H), 3.70-3.59 (m, 1H), 3.54-3.41 (m, 1H), 2.12-2.02 (m, 1H), 1.83-1.73(m, 2H), 1.70-1.58 (m, 1H).

LC-MS (Method 3): R_(t)=2.13 min; 609 [M+H]⁺.

Example 252rac-1-(2,4-Difluorophenyl)-N-[1-(2,6-difluorophenyl)-2,2,2-trifluoroethyl]-7-[4-hydroxy-2-oxopiperidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP2, 150 mg (283 μmol) of the compound from Example 80Awere reacted with 39.1 mg (340 μmol) of rac-4-hydroxypiperidin-2-one inthe presence of 58.7 mg (425 μmol) of potassium carbonate, 13 mg (57μmol) of palladium(II) acetate and 33 mg (57 μmol) of Xantphos in 2.5 mlof dioxane. The crude product was purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×40 mm, solvent: acetonitrile/0.1%formic acid gradient; (0 to 3 min. 10% acetonitrile to 40 min. 90%acetonitrile and a further 3 min. 90% acetonitrile), and 113 mg (65% oftheory, 100% purity) of the title compound were obtained.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=11.38-11.31 (m, 1H), 8.89 (s, 1H),8.67 (d, 1H), 8.15-8.08 (m, 1H), 7.94-7.76 (m, 1H), 7.68-7.56 (m, 2H),7.41-7.24 (m, 3H), 6.51-6.38 (m, 1H), 5.10-5.01 (m, 1H), 4.11-4.01 (m,1H), 3.69-3.57 (m, 1H), 3.50-3.38 (m, 1H), 2.84-2.72 (m, 1H), 2.46-2.37(m, 1H), 1.99-1.87 (m, 1H), 1.78-1.66 (m, 1H).

LC-MS (Method 3): R_(t)=2.12 min; 609 [M+H]⁺.

100 mg of the title compound (racemic diastereomer mixture) wereseparated into the enantiomeric diastereomers by chiral HPLC(preparative HPLC: column: Daicel Chiralpak ID 5 μm 250×50 mm; eluent:50% isohexane, 20% ethanol; temperature: 40° C.; flow rate: 15 ml/min;UV detection: 220 nm).

This gave (in the sequence of elution from the column) 22 mg ofdiastereomer 1 (99% de) R_(t)=8.70 min, 24 mg (99% de) of diastereomer 2R_(t)=11.80 min, 24 mg (99.5% de) of diastereomer 3 R_(t)=6.47 min, and24 mg (99.5% de) of diastereomer 4 R_(t)=5.94 min.

[Analytical HPLC: column: Daicel Chiralcel OZ-H 5 μm 250×4.6 mm; eluent:50% isohexane, 50% ethanol; temperature: 40° C.; flow rate: 1 ml/min; UVdetection: 220 nm]

Example 2531-(2,4-Difluorophenyl)-N-[1-(2,6-difluorophenyl)-2,2,2-trifluoroethyl]-7-[4-hydroxy-2-oxopiperidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=11.39-11.31 (m, 1H), 8.89 (s, 1H),8.67 (d, 1H), 8.15-8.09 (m, 1H), 7.94-7.76 (m, 1H), 7.68-7.57 (m, 2H),7.41-7.27 (m, 3H), 6.51-6.39 (m, 1H), 5.10-5.04 (m, 1H), 4.12-4.01 (m,1H), 3.69-3.59 (m, 1H), 3.48-3.38 (m, 1H), 2.83-2.72 (m, 1H), 2.47-2.37(m, 1H), 1.99-1.88 (m, 1H), 1.79-1.67 (m, 1H).

LC-MS (Method 3): R_(t)=1.99 min; 609 [M+H]⁺.

Example 2541-(2,4-Difluorophenyl)-N-[1-(2,6-difluorophenyl)-2,2,2-trifluoroethyl]-7-[4-hydroxy-2-oxopiperidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2)

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=11.34 (br. d, 1H), 8.89 (s, 1H), 8.67(d, 1H), 8.15-8.09 (m, 1H), 7.93-7.76 (m, 1H), 7.68-7.57 (m, 2H),7.40-7.26 (m, 3H), 6.50-6.39 (m, 1H), 5.10-5.02 (m, 1H), 4.12-4.01 (m,1H), 3.68-3.57 (m, 1H), 3.50-3.39 (m, 1H), 2.84-2.72 (m, 1H),2.47-2.37-(m, 1H), 2.00-1.88 (m, 1H), 1.78-1.66 (m, 1H).

LC-MS (Method 3): R_(t)=2.00 min; 609 [M+H]⁺.

Example 2551-(2,4-Difluorophenyl)-N-[1-(2,6-difluorophenyl)-2,2,2-trifluoroethyl]-7-[4-hydroxy-2-oxopiperidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(3rd Diastereomer)

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=11.38-11.32 (m, 1H), 8.89 (s, 1H),8.67 (d, 1H), 8.16-8.07 (m, 1H), 7.95-7.75 (m, 1H), 7.68-7.57 (m, 2H),7.41-7.26 (m, 3H), 6.51-6.39 (m, 1H), 5.11-5.02 (m, 1H), 4.11-4.01 (m,1H), 3.69-3.58 (m, 1H), 3.48-3.38 (m, 1H), 2.84-2.72 (m, 1H), 2.48-2.37(m, 1H), 2.00-1.88 (m, 1H), 1.79-1.67 (m, 1H).

LC-MS (Method 3): R_(t)=1.99 min; 609 [M+H]⁺.

Example 2561-(2,4-Difluorophenyl)-N-[1-(2,6-difluorophenyl)-2,2,2-trifluoroethyl]-7-[4-hydroxy-2-oxopiperidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(4th Diastereomer)

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=11.35 (d, 1H), 8.89 (s, 1H), 8.67 (d,1H), 8.15-8.09 (m, 1H), 7.93-7.77 (m, 1H), 7.68-7.58 (m, 2H), 7.40-7.28(m, 3H), 6.50-6.39 (m, 1H), 5.10-5.04 (m, 1H), 4.11-4.02 (m, 1H),3.68-3.58 (m, 1H), 3.50-3.39 (m, 1H), 2.83-2.73 (m, 1H), 2.47-2.37 (m,1H), 1.99-1.88 (m, 1H), 1.78-1.67 (m, 1H).

LC-MS (Method 3): R_(t)=2.00 min; 609 [M+H]⁺.

Example 257 Methyl(5S)-3-[8-(2,4-difluorophenyl)-5-oxo-6-{[(2R)-1,1,1-trifluorobutan-2-yl]carbamoyl}-5,8-dihydro-1,8-naphthyridin-2-yl]-2-oxo-1,3-oxazolidine-5-carboxylate

According to GP2, 100 mg (224 μmol) of the compound from Example 67Awere reacted with 39.1 mg (269 μmol) of the compound from Example 96 inthe presence of 46.5 mg (269 μmol) of potassium carbonate, 10 mg (45μmol) of palladium(II) acetate and 26 mg (45 μmol) of Xantphos in 2 mlof 1,4-dioxane. The crude product was diluted with acetonitrile andwater and purified by means of preparative HPLC (column: ChromatorexC18, 10 μm, 125×40 mm, solvent: acetonitrile/0.05% formic acid gradient;(0 to 3 min. 10% acetonitrile to 40 min. 90% acetonitrile and a further3 min. 90% acetonitrile), and 101 mg (81% of theory, 100% purity) of thetitle compound were obtained.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=0.98 (t, 3H), 1.60-1.72 (m, 1H),1.84-1.95 (m, 1H), 3.73 (d, 3H), 3.77-3.89 (m, 1H), 3.96-4.08 (m, 1H),4.70-4.83 (m, 1H), 5.23-5.32 (m, 1H), 7.37 (td, 1H), 7.63 (br. t, 1H),7.82-7.93 (m, 1H), 8.26 (dd, 1H), 8.75 (d, 1H), 8.86 (d, 1H), 10.18 (d,1H).

LC-MS (Method 2): R_(t)=2.07 min; 555 [M+H]⁺.

Example 258 Methyl(5S)-3-[8-(2,4-difluorophenyl)-5-oxo-6-{[(2S)-1,1,1-trifluorobutan-2-yl]carbamoyl}-5,8-dihydro-1,8-naphthyridin-2-yl]-2-oxo-1,3-oxazolidine-5-carboxylate

According to GP2, 500 mg (1.12 mmol, 94% purity) of the compound fromExample 68A were reacted with 195 mg (1.35 mmol) of the compound fromExample 96 in the presence of 233 mg (1.68 mmol) of potassium carbonate,50.4 mg (224 μmol) of palladium(II) acetate and 130 mg (224 μmol) ofXantphos in 10 ml of 1,4-dioxane. The crude product was diluted withacetonitrile and water and purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×40 mm, solvent: acetonitrile/0.05%formic acid gradient; (0 to 3 min. 10% acetonitrile to 40 min. 90%acetonitrile and a further 3 min. 90% acetonitrile), and 504 mg (81% oftheory, 100% purity) of the title compound were obtained.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=0.98 (t, 3H), 1.60-1.74 (m, 1H),1.83-1.97 (m, 1H), 3.73 (d, 3H), 3.77-3.89 (m, 1H), 3.96-4.08 (m, 1H),4.70-4.85 (m, 1H), 5.22-5.31 (m, 1H), 7.32-7.41 (m, 1H), 7.63 (td, 1H),7.88 (td, 1H), 8.26 (t, 1H), 8.75 (d, 1H), 8.86 (s, 1H), 10.18 (d, 1H).

LC-MS (Method 1): R_(t)=1.13 min; 555 [M+H]⁺.

Example 259 Methyl(5R)-3-[8-(2,4-difluorophenyl)-5-oxo-6-{[(2S)-1,1,1-trifluorobutan-2-yl]carbamoyl}-5,8-dihydro-1,8-naphthyridin-2-yl]-2-oxo-1,3-oxazolidine-5-carboxylate

According to GP2, 500 mg (1.12 mmol, 94% purity) of the compound fromExample 68A were reacted with 195 mg (1.35 mmol) of the compound fromExample 99 in the presence of 233 mg (1.68 mmol) of potassium carbonate,50.4 mg (224 μmol) of palladium(II) acetate and 130 mg (224 μmol) ofXantphos in 10 ml of 1,4-dioxane. The crude product was diluted withacetonitrile and water and purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×40 mm, solvent: acetonitrile/0.05%formic acid gradient; (0 to 3 min. 10% acetonitrile to 40 min. 90%acetonitrile and a further 3 min. 90% acetonitrile), and 497 mg (80% oftheory, 100% purity) of the title compound were obtained.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=0.98 (t, 3H), 1.59-1.74 (m, 1H),1.83-1.96 (m, 1H), 3.73 (d, 3H), 3.77-3.89 (m, 1H), 3.96-4.09 (m, 1H),4.70-4.84 (m, 1H), 5.23-5.32 (m, 1H), 7.32-7.41 (m, 1H), 7.57-7.68 (m,1H), 7.82-7.94 (m, 1H), 8.26 (dd, 1H), 8.75 (d, 1H), 10.18 (d, 1H), 8.86(d, 1H).

LC-MS (Method 1): R_(t)=1.14 min; 555 [M+H]⁺.

Example 260rac-1-(2,6-Difluorophenyl)-7-[5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 40 mg (89.7 μmol, 99% purity) of the compound fromExample 86A were reacted with 12.6 mg (108 μmol) ofrac-5-(hydroxymethyl)-1,3-oxazolidin-2-one in the presence of 18.6 mg(135 μmol) of potassium carbonate, 4.0 mg (18 μmol) of palladium(II)acetate and 10 mg (18 μmol) of Xantphos in 1 ml of 1,4-dioxane. Thereaction mixture was diluted with acetonitrile and water, filtered andpurified by means of preparative HPLC (column: Chromatorex C18, 10 μm,125×40 mm, solvent: acetonitrile/0.05% formic acid gradient; (0 to 3min. 10% acetonitrile to 40 min. 90% acetonitrile and a further 3 min.90% acetonitrile) and additionally by means of flash chromatography(cyclohexane/ethyl acetate gradient), and 10 mg (21% of theory, 100%purity) of the title compound were obtained.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=0.98 (t, 3H), 1.59-1.75 (m, 1H),1.83-1.96 (m, 1H), 3.42-3.55 (m, 2H), 3.56-3.66 (m, 1H), 3.75 (t, 1H),4.62-4.71 (m, 1H), 4.72-4.83 (m, 1H), 5.18 (t, 1H), 7.39-7.50 (m, 2H),7.69-7.80 (m, 1H), 8.34 (d, 1H), 8.73 (d, 1H), 9.01 (s, 1H), 10.12 (d,1H).

LC-MS (Method 2): R_(t)=1.88 min; 527 [M+H]⁺.

Example 2611-(2,4-Difluorophenyl)-7-(3-hydroxyazetidin-1-yl)-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP3, 50.0 mg (112 μmol) of the compound from Example 67Awere reacted with 14.7 mg (135 μmol) of 3-hydroxyazetidine hydrochlorideand 68 μl (0.39 mmol) of N,N-diisopropylamine in 0.5 ml ofdimethylformamide. The reaction solution was diluted with 0.5 ml each ofacetonitrile and water and purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient; 0 to 3 min 10% acetonitrile, to 40 min 90%acetonitrile and for a further 3 min 90% acetonitrile). 50.7 mg (93% oftheory, 99% purity) of the title compound were obtained.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=0.96 (t, 3H), 1.57-1.70 (m, 1H),1.82-1.94 (m, 1H), 3.50-3.81 (br. m, 2H), 3.89-4.32 (br. m, 2H),4.49-4.57 (m, 1H), 4.67-4.80 (m, 1H), 5.72 (d, 1H), 6.60 (d, 1H),7.28-7.34 (m, 1H), 7.52-7.60 (m, 1H), 7.75-7.84 (m, 1H), 8.28 (d, 1H),8.61 (s, 1H), 10.48 (d, 1H).

LC-MS (Method 1): R_(t)=1.00 min; 483 [M+H]⁺.

Example 2621-(2,4-Difluorophenyl)-7-[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP3, 50.0 mg (112 μmol) of the compound from Example 67Awere reacted with 19.0 mg (135 μmol) of 3-(trifluoromethyl)azetidin-3-oland 68 μl (0.39 mmol) of N,N-diisopropylethylamine in 0.5 ml ofdimethylformamide. The reaction solution was diluted with 0.5 ml ofacetonitrile and purified by means of preparative HPLC (column:Chromatorex C18, 10 m, 125×30 mm, solvent: acetonitrile/0.05% formicacid gradient; (0 to 3 min. 10% acetonitrile to 40 min. 90% acetonitrileand a further 3 min. 90% acetonitrile), and 51.9 mg (83% of theory, 99%purity) of the title compound were obtained.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=0.97 (t, 3H). 1.57-1.71 (m, 1H),1.82-1.94 (m, 1H), 3.67-4.51 (br. m, 4H), 4.68-4.81 (m, 1H), 6.75 (d,1H), 7.29-7.36 (m, 1H), 7.43 (s, 1H), 7.54-7.62 (m, 1H), 7.77-7.86 (m,1H), 8.38 (d, 1H), 8.66 (s, 1H), 10.42 (d, 1H).

LC-MS (Method 3): R_(t)=2.14 min; 551 [M+H]⁺.

Example 2637-[2-(Difluoromethyl)morpholin-4-yl]-1-(2,4-difluorophenyl)-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP3, 100 mg (224 μmol) of the compound from Example 67Awere reacted with 36.9 mg (269 μmol) of rac-2-(difluoromethyl)morpholineand 137 μl (785 μmol) of N,N-diisopropylethylamine in 1 ml ofdimethylformamide. The reaction solution was purified by means ofpreparative HPLC (column: Chromatorex C18, 10 m, 125×30 mm, solvent:acetonitrile/0.05% formic acid gradient; (0 to 3 min. 10% acetonitrileto 40 min. 90% acetonitrile and a further 3 min. 90% acetonitrile), and103 mg (83% of theory, 99% purity) of the title compound were obtained.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=0.97 (t, 3H), 1.57-1.71 (m, 1H),1.83-1.94 (m, 1H), 2.83-2.96 (m, 1H), 3.05-3.16 (m, 1H), 3.48-3.58 (m,1H), 3.63-3.74 (m, 1H), 3.91-4.04 (m, 2H), 4.07-4.16 (m, 1H), 4.70-4.79(m, 1H), 6.02 (t, 1H), 7.16 (d, 1H), 7.27-7.35 (m, 1H), 7.48-7.70 (m,1H), 7.77-7.86 (m, 1H), 8.36 (d, 1H), 8.66-8.69 (m, 1H), 10.43 (d, 1H).

LC-MS (Method 3): R_(t)=2.19 min; 547 [M+H]⁺.

98 mg of the title compound (diastereomer mixture) were separated intothe diastereomers by chiral HPLC (preparative HPLC: column: DaicelChiralcel OX-H 5 m 250×20 mm; eluent: 25% ethanol, 75% isohexane;temperature: 40° C.; flow rate: 15 ml/min; UV detection: 220 nm).

This gave (in the sequence of elution from the column) 46 mg ofdiastereomer 1 (99% de) R_(t)=6.27 min and 46 mg (99% de) ofdiastereomer 2 R_(t)=7.92 min.

[Analytical HPLC: column: Chiralcel OX-3 5 m 50×4.6 mm; eluent: 30%ethanol, 70% isohexane; temperature: 30° C.; flow rate: 1.0 ml/min; UVdetection: 220 nm]

Diastereomer 1 (Example 264) was additionally purified by means ofpreparative HPLC (column: Chromatorex C18, 10 m, 125×30 mm, solvent:acetonitrile/0.05% formic acid gradient; (0 to 3 min. 10% acetonitrileto 35 min. 90% acetonitrile and a further 3 min. 90% acetonitrile)), and38.4 mg (31% of theory, 99% purity) of the title compound from Example264 were obtained.

Diastereomer 2 (Example 265) was additionally purified by means ofpreparative HPLC (column: Chromatorex C18, 10 m, 125×30 mm, solvent:acetonitrile/0.05% formic acid gradient; (0 to 3 min. 10% acetonitrileto 35 min. 90% acetonitrile and a further 3 min. 90% acetonitrile)), and40.1 mg (32% of theory, 99% purity) of the title compound from Example265 were obtained.

Example 2647-[2-(Difluoromethyl)morpholin-4-yl]-1-(2,4-difluorophenyl)-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=0.97 (t, 3H). 1.57-1.71 (m, 1H),1.82-1.95 (m, 1H), 2.82-2.97 (m, 1H), 3.04-3.17 (m, 1H), 3.47-3.59 (m,1H), 3.63-3.75 (m, 1H), 3.91-4.04 (m, 2H), 4.07-4.16 (m, 1H), 4.68-4.81(m, 1H), 6.02 (t, 1H), 7.16 (d, 1H), 7.27-7.36 (m, 1H), 7.48-7.60 (m,1H), 7.77-7.85 (m, 1H), 8.36 (d, 1H), 8.67 (d, 1H), 10.43 (d, 1H).

LC-MS (Method 3): Rt=2.20 min; 547 [M+H]⁺.

Example 2657-[2-(Difluoromethyl)morpholin-4-yl]-1-(2,4-difluorophenyl)-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2)

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=0.97 (t, 3H), 1.57-1.71 (m, 1H),1.81-1.95 (m, 1H), 2.82-2.96 (m, 1H), 3.04-3.16 (m, 1H), 3.46-3.58 (m,1H), 3.62-3.75 (m, 1H), 3.89-4.04 (m, 2H), 4.07-4.16 (m, 1H), 4.67-4.81(m, 1H), 6.02 (t, 1H), 7.16 (d, 1H), 7.26-7.36 (m, 1H), 7.47-7.60 (m,1H), 7.77-7.86 (m, 1H), 8.36 (d, 1H), 8.67 (d, 1H), 10.43 (d, 1H).

LC-MS (Method 3): Rt=2.20 min; 547 [M+H]⁺.

Example 2661-(2,4-Difluorophenyl)-7-[5-methyl-2-oxo-1,3-oxazolidin-3-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP2, 100 mg (222 μmol) of the compound from Example 67Awere reacted with 26.9 mg (266 μmol) ofrac-5-methyl-1,3-oxazolidin-2-one in the presence of 36.8 mg (266 μmol)of potassium carbonate, 3.5 mg (16 μmol) of palladium(II) acetate and 26mg (44 μmol) of Xantphos in 2 ml of 1,4-dioxane. The solvent was removedunder reduced pressure and the residue was taken up in 3 ml ofacetonitrile and 1 ml of DMSO. The precipitate was filtered off withsuction and dried under high vacuum, and 24.5 mg (21.6% of theory, 100%purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=0.98 (t, 3H). 1.31-1.40 (m, 3H),1.60-1.72 (m, 1H), 1.83-1.93 (m, 1H), 3.83-3.95 (m, 1H), 4.69-4.84 (m,2H), 7.31-7.39 (m, 1H), 7.55-7.66 (m, 1H), 7.82-7.92 (m, 1H), 8.32 (d,1H), 8.72 (d, 1H), 8.84 (s, 1H), 10.21 (d, 1H).

LC-MS (Method 1): R_(t)=1.14 min; 511 [M+H]⁺.

Example 2671-(2,4-Difluorophenyl)-7-[1-hydroxy-3-azabicyclo[3.1.0]hex-3-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP3, 50.0 mg (112 μmol) of the compound from Example 67Awere reacted with 19.2 mg (135 μmol) ofrac-3-azabicyclo[3.1.0]hexan-1-ol hydrochloride and 68.0 μl (393 μmol)of N,N-diisopropylamine in 0.5 ml of dimethylformamide. The reactionsolution was diluted with 0.5 ml of acetonitrile and purified by meansof preparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm, solvent:acetonitrile/0.05% formic acid gradient; (0 to 3 min. 10% acetonitrileto 40 min. 90% acetonitrile and a further 3 min. 90% acetonitrile), and41.4 mg (72% of theory, 99% purity) of the title compound were obtained.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=0.32-0.50 (m, 1H). 0.89-1.09 (m, 4H),1.50-1.72 (m, 2H), 1.81-1.94 (m, 1H), 3.04-3.95 (m, 4H), 4.66-4.81 (m,1H), 6.01 (d, 1H), 6.66-6.82 (m, 1H), 7.27-7.38 (m, 1H), 7.52-7.66 (m,1H), 7.75-7.86 (m, 1H), 8.28 (d, 1H), 8.62 (s, 1H), 10.48 (d, 1H).

LC-MS (Method 3): R_(t)=1.98 min; 509 [M+H]⁺.

35 mg of the title compound (diastereomer mixture) were separated intothe diastereomers by chiral HPLC (preparative HPLC: column: DaicelChiralcel OZ-H 5 μm 250×20 mm; eluent: 25% 2-propanol, 75% isohexane;temperature: 25° C.; flow rate: 15 ml/min; UV detection: 210 nm).

This gave (in the sequence of elution from the column) 15.4 mg ofdiastereomer 1 (100% de) R_(t)=1.34 min and 20.1 mg (97% de) ofdiastereomer 2 R_(t)=1.59 min.

[Analytical HPLC: column: Daicel Chiralpak OZ-3 3 μm 50×4.6 mm; eluent:20% ethanol, 80% isohexane; flow rate: 1 ml/min; UV detection: 220 nm].

Diastereomer 1 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90%acetonitrile and a further 3 min. 90% acetonitrile)), and 8.8 mg (15% oftheory, 99% purity) of the title compound from Example 314 wereobtained.

Diastereomer 2 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90%acetonitrile and a further 3 min. 90% acetonitrile)), and 8.4 mg (15% oftheory, 99% purity) of the title compound from Example 315 wereobtained.

Example 2687-[(4S)-4-Hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1-[2-(trifluoromethyl)phenyl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Atropisomer Mixture)

According to GP2, 55.0 mg (115 μmol) of the compound from Example 92Awere reacted with 11.6 mg (115 μmol) of (4S)-4-hydroxypyrrolidin-2-onein the presence of 56.3 mg (173 μmol) of caesium carbonate, 4.7 mg (21μmol) of palladium(II) acetate and 24 mg (41 μmol) of Xantphos in 2.3 mlof 1,4-dioxane. Subsequently, the mixture was diluted with 3 ml ofacetonitrile and 0.5 ml of water, filtered and purified by means ofpreparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm, solvent:acetonitrile/0.05% formic acid gradient; 0 to 3 min 10% acetonitrile, to35 min 90% acetonitrile and for a further 3 min 90% acetonitrile). 22 mg(35% of theory, 99% purity) of the title compound were obtained as amixture of the atropisomers.

In analogy to the experimental procedure described in A, 56 mg (117μmol) of the compound from Example 93A were reacted with 11.9 mg (117μmol) of (4S)-4-hydroxypyrrolidin-2-one in the presence of 57.3 mg (176μmol) of caesium carbonate, 4.7 mg (21 μmol) of palladium(II) acetateand 24 mg (41 μmol) of Xantphos in 2.3 ml of 1,4-dioxane. Subsequently,the mixture was diluted with 3 ml of acetonitrile and 0.5 ml of water,filtered and purified by means of preparative HPLC (column: ChromatorexC18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05% formic acid gradient;0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrile and for afurther 3 min 90% acetonitrile). 27 mg (42% of theory, 99% purity) ofthe title compound were obtained as a mixture of the atropisomers.

The mixture of the atropisomers A and B was combined and the combinedbatch was then separated into the atropisomers by chiral HPLC(preparative HPLC: column: Daicel Chiralcel OZ-H 5 μm 250×20 mm; eluent:30% ethanol, 70% isohexane; temperature: 25° C.; flow rate: 15 ml/min;UV detection: 220 nm). This gave (in the sequence of elution from thecolumn) 22 mg of atropisomer 1 (90% de) R_(t)=3.99 min and 18 mg (83%de) of atropisomer 2 R_(t)=4.79 min.

[Analytical HPLC: column: Daicel Chiralpak AZ-H 5 m 250×4.6 mm; eluent:30% ethanol, 70% isohexane with 0.2% diethylamine; temperature: 50° C.;flow rate: 1.0 ml/min; UV detection: 270 nm]

Atropisomer 1 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90%acetonitrile and a further 3 min. 90% acetonitrile)), and 16.8 mg (26.6%of theory, 99% purity) of the title compound from Example 269 wereobtained.

Atropisomer 2 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90%acetonitrile and a further 3 min. 90% acetonitrile)), and 20.1 mg (32%of theory, 99% purity) of the title compound from Example 270 wereobtained.

Example 2697-[(4S)-4-Hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1-[2-(trifluoromethyl)phenyl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Atropisomer 1)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.97 (t, 3H), 1.59-1.73 (m, 1H),1.83-1.95 (m, 1H), 2.32 (d, 1H), 2.93 (dd, 1H), 3.47 (dd, 1H), 4.17-4.23(m, 1H), 4.70-4.82 (m, 1H), 5.27 (d, 1H), 7.91-7.84 (m, 2H), 7.95-8.00(m, 1H), 8.02-8.07 (m, 1H), 8.51 (d, 1H), 8.71 (d, 1H), 8.82 (s, 1H),10.24 (d, 1H).

LC-MS (Method 3): R_(t)=1.88 min; 543 [M+H]⁺.

Example 2707-[(4S)-4-Hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1-[2-(trifluoromethyl)phenyl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Atropisomer 2)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.99 (t, 3H), 1.61-1.75 (m, 1H),1.84-1.96 (m, 1H), 2.34 (d, 1H), 2.89 (dd, 1H), 3.25 (d, 1H), 3.47 (dd,1H), 4.17-4.24 (m, 1H), 4.69-4.83 (m, 1H), 5.29 (d, 1H), 7.82-7.91 (m,2H), 7.93-7.99 (m, 1H), 8.02-8.07 (m, 1H), 8.49 (d, 1H), 8.71 (d, 1H),8.81 (s, 1H), 10.23 (d, 1H).

LC-MS (Method 3): R_(t)=1.87 min; 543 [M+H]⁺.

Example 271N-[(1R)-1-Cyclopropyl-2,2,2-trifluoroethyl]-1-(2,4-difluorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 74.0 mg (167 μmol, 90.8% purity) of the compound fromExample 63A were reacted with 32.3 mg (184 μmol) of(R)-1-cyclopropyl-2,2,2-trifluoroethanamine hydrochloride (J. Med. Chem.2011, 54, 7334-7349) in the presence of 63.7 mg (167 μmol) of HATU and70 μl (0.40 mmol) of N,N-diisopropylethylamine in 0.9 ml ofdimethylformamide. 1 ml of 1M aqueous hydrochloric acid and 10 ml ofwater were added and the mixture was extracted three times with 10 ml ofethyl acetate. The combined organic phases were dried over magnesiumsulphate and filtered, and the solvent was removed under reducedpressure. The residue was taken up in a little DCM and purified by meansof flash chromatography (cyclohexane/ethyl acetate gradient). 75.3 mg(86% of theory, 100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.29-0.38 (m, 1H). 0.51-0.71 (m, 3H),1.18-1.28 (m, 1H), 2.31-2.42 (m, 1H), 2.87-3.00 (m, 1H), 3.42-3.52 (m,1H), 3.61-3.72 (m, 1H), 4.25-4.32 (m, 1H), 4.34-4.49 (m, 1H), 5.32 (dd,1H), 7.41-7.33 (m, 1H), 7.59-7.67 (m, 1H), 7.83-7.92 (m, 1H), 8.49-8.55(m, 1H), 8.71 (d, 1H), 8.84 (s, 1H), 10.36 (dd, 1H).

LC-MS (Method 3): R_(t)=1.89 min; 523 [M+H]⁺.

Example 2721-(2,4-Difluorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[2,2,2-trifluoro-1-(3-fluorophenyl)ethyl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP1, 170 mg (352 μmol, 83% purity) of the compound fromExample 63A were reacted with 102 mg (527 μmol) ofrac-2,2,2-trifluoro-1-(3-fluorophenyl)ethanamine in the presence of 134mg (352 μmol) of HATU and 86 μl (0.49 mmol) of N,N-diisopropylethylaminein 3.5 ml of dimethylformamide. 1 ml of 1M aqueous hydrochloric acid and10 ml of water were added and the mixture was extracted three times with10 ml of ethyl acetate. The combined organic phases were dried overmagnesium sulphate and filtered, and the solvent was removed underreduced pressure. The residue was taken up in a little DCM and purifiedby means of flash chromatography (cyclohexane/ethyl acetate gradient).107 mg (53% of theory, 100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=2.31-2.42, 2.88-3.00 (m, 1H),3.41-3.52 (m, 1H), 3.61-3.72 (m, 1H), 4.25-4.32 (m, 1H), 5.32 (d, 1H),6.15-6.25 (m, 1H), 7.27-7.49 (m, 4H), 7.52-7.68 (m, 2H), 7.76-7.94 (m,1H), 8.51-8.57 (m, 1H), 8.77 (d, 1H), 8.87 (s, 1H), 11.21 (d, 1H).

LC-MS (Method 3): R_(t)=2.04 min; 577 [M+H]⁺.

Example 2731-(2,4-Difluorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[2,2,2-trifluoro-1-(4-fluorophenyl)ethyl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP1, 170 mg (352 μmol, 83% purity) of the compound fromExample 63A were reacted with 81.5 mg (422 μmol) ofrac-2,2,2-trifluoro-1-(4-fluorophenyl)ethanamine in the presence of 134mg (352 μmol) of HATU and 86 μl (0.49 mmol) of N,N-diisopropylethylaminein 3.5 ml of dimethylformamide. 1 ml of 1M aqueous hydrochloric acid and10 ml of water were added and the mixture was extracted three times with10 ml of ethyl acetate. The combined organic phases were washed withsaturated aqueous sodium chloride solution, dried over magnesiumsulphate and filtered, and the solvent was removed under reducedpressure. The residue was taken up in a little dichloromethane andpurified by means of flash chromatography (cyclohexane/ethyl acetategradient). 98 mg (48% of theory, 100% purity) of the title compound wereobtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=2.32-2.42 (m, 1H). 2.88-3.00 (m, 1H),3.42-3.52 (m, 1H), 3.61-3.72 (m, 1H), 4.25-4.32 (m, 1H), 5.32 (d, 1H),6.09-6.21 (m, 1H), 7.30-7.42 (m, 3H), 7.58-7.68 (m, 3H), 7.77-7.93 (m,1H), 8.51-8.57 (m, 1H), 8.76 (d, 1H), 8.86 (s, 1H), 11.20 (d, 1H).

LC-MS (Method 3): R_(t)=2.03 min; 577 [M+H]⁺.

Example 274N-[1-(3-Chlorophenyl)-2,2,2-trifluoroethyl]-1-(2,4-difluorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP1, 170 mg (352 μmol, 83% purity) of the compound fromExample 63A were reacted with 88.4 mg (422 μmol) ofrac-1-(3-chlorophenyl)-2,2,2-trifluoroethanamine in the presence of 134mg (352 μmol) of HATU and 86 μl (0.49 mmol) of N,N-diisopropylethylaminein 3.5 ml of dimethylformamide. 1 ml of 1 M aqueous hydrochloric acidand 10 ml of water were added and the mixture was extracted three timeswith 10 ml of ethyl acetate. The combined organic phases were washedwith saturated aqueous sodium chloride solution, dried over magnesiumsulphate and filtered, and the solvent was removed under reducedpressure. The residue was taken up in a little dichloromethane andpurified by means of flash chromatography (cyclohexane/ethyl acetategradient). 127 mg (61% of theory, 100% purity) of the title compoundwere obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=2.31-2.42 (m, 1H), 2.87-3.01 (m, 1H),3.42-3.53 (m, 1H), 3.60-3.73 (m, 1H), 4.25-4.32 (m, 1H), 5.32 (d, 1H),6.15-6.25 (m, 1H), 7.31-7.41 (m, 1H), 7.51-7.71 (m, 5H), 7.77-7.94 (m,1H), 8.51-8.57 (m, 1H), 8.77 (d, 1H), 8.86 (s, 1H), 11.22 (d, 1H).

LC-MS (Method 3): R_(t)=2.15 min; 593 [M+H]⁺.

Example 2751-(2,6-Difluorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 100 mg (224 μmol) of the compound from Example 86Awere reacted with 22.7 mg (224 μmol) of (4S)-4-hydroxypyrrolidin-2-onein the presence of 109 mg (336 μmol) of caesium carbonate, 9.1 mg (40μmol) of palladium(II) acetate and 47 mg (81 μmol) of Xantphos in 5 mlof 1,4-dioxane. This was followed by dilution with 2 ml of acetonitrileand 0.5 ml of water, filtration and purification by means of preparativeHPLC (column: Chromatorex C18, 10 μm, 125×30 mm, solvent:acetonitrile/0.05% formic acid gradient; (0 to 3 min. 10% acetonitrileto 35 min. 90% acetonitrile and a further 3 min. 90% acetonitrile), and33.2 mg (29% of theory, 99% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.99 (t, 3H). 1.60-1.74 (m, 1H),1.84-1.96 (m, 1H), 2.37 (d, 1H), 2.93 (dd, 1H), 3.43 (d, 1H), 3.64 (dd,1H), 4.21-4.30 (m, 1H), 4.70-4.83 (m, 1H), 5.32 (d, 1H), 7.42-7.50 (m,2H), 7.72-7.81 (m, 1H), 8.54 (d, 1H), 8.72 (d, 1H), 9.02 (s, 1H), 10.13(d, 1H).

LC-MS (Method 3): R_(t)=1.86 min; 511 [M+H]⁺.

Example 2761-(2,6-Difluorophenyl)-7-[3-hydroxy-3-methylpyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP3, 100 mg (224 μmol) of the compound from Example 86Awere reacted with 41.2 mg (269 μmol, 90% purity) ofrac-3-methylpyrrolidin-3-ol hydrochloride and 137 μl (785 μmol) ofN,N-diisopropylethylamine in 1 ml of dimethylformamide. The mixture wasdiluted with 0.5 ml of acetonitrile and the crude solution was purifiedby means of preparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm,solvent: acetonitrile/0.05% formic acid gradient; (0 to 3 min. 10%acetonitrile to 40 min. 90% acetonitrile and a further 3 min. 90%acetonitrile), and 96.4 mg (83% of theory, 99% purity) of the titlecompound were obtained.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=0.97 (t, 3H), 1.22/1.31 (2×s, 3H),1.57-1.72 (m, 1H), 1.72-1.80 (m, 1H), 1.82-1.95 (m, 2H), 2.90/3.09 (2×d,1H), 3.13-3.21 (m, 1H), 3.23-3.40 (m, 1H, partially under the DMSOpeak), 3.49-3.59 (m, 1H), 4.67-4.79 (m, 1H), 4.84 (d, 1H), 6.74 (dd,1H), 7.36-7.46 (m, 2H), 7.65-7.76 (m, 1H), 8.24-8.31 (m, 1H), 8.73 (d,1H), 10.45 (d, 1H).

LC-MS (Method 3): R_(t)=2.00 min; 511 [M+H]⁺.

90 mg of the title compound (diastereomer mixture) were separated intothe diastereomers by chiral HPLC (preparative HPLC: column: DaicelChiralpak IE-H 5 μm 250×20 mm; eluent: 20% ethanol, 80% isohexane;temperature: 25° C.; flow rate: 15 ml/min; UV detection: 220 nm).

This gave (in the sequence of elution from the column) 43 mg ofdiastereomer 1 (99% de) R_(t)=6.98 min and 45 mg (94% de) ofdiastereomer 2 R_(t)=7.36 min.

[Analytical HPLC: column: Chiralpak IE-3 5 μm 250×4.6 mm; eluent: 25%ethanol, 75% isohexane; temperature: 30° C.; flow rate: 1.0 ml/min; UVdetection: 220 nm]

Diastereomer 1 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90%acetonitrile and a further 3 min. 90% acetonitrile)), and 35.8 mg (31%of theory, 99% purity) of the title compound from Example 276 wereobtained.

Diastereomer 2 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90%acetonitrile and a further 3 min. 90% acetonitrile)), and 36.0 mg (31%of theory, 99% purity) of the title compound from Example 277 wereobtained.

Example 2771-(2,6-Difluorophenyl)-7-[3-hydroxy-3-methylpyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=0.97 (t, 3H), 1.22/1.31 (2×s, 3H),1.58-1.71 (m, 1H), 1.73-1.80 (m, 1H), 1.83-1.94 (m, 2H), 2.91/3.09 (2×d,1H), 3.13-3.21 (m, 1H), 3.27-3.39 (m, 1H, partially under the DMSOpeak), 3.51-3.58 (m, 1H), 4.67-4.78 (m, 1H), 4.85 (d, 1H), 6.74 (dd,1H), 7.37-7.45 (m, 2H), 7.65-7.76 (m, 1H), 8.24-8.31 (m, 1H), 8.74 (d,1H), 10.45 (d, 1H).

LC-MS (Method 3): R_(t)=2.01 min; 511 [M+H]⁺.

Example 2781-(2,6-Difluorophenyl)-7-[3-hydroxy-3-methylpyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2)

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=0.97 (t, 3H). 1.22/1.31 (2×s, 3H),1.57-1.71 (m, 1H), 1.73-1.80 (m, 1H), 1.82-1.95 (m, 2H), 2.91/3.09 (2×d,1H), 3.13-3.21 (m, 1H), 3.26-3.39 (m, 1H, partially under the DMSOpeak), 3.50-3.57 (m, 1H), 4.67-4.79 (m, 1H), 4.85 (d, 1H), 6.74 (dd,1H), 7.37-7.46 (m, 2H), 7.65-7.76 (m, 1H), 8.24-8.32 (m, 1H), 8.74 (d,1H), 10.45 (d, 1H),

LC-MS (Method 3): R_(t)=2.01 min; 511 [M+H]⁺.

Example 2791-(2-Chlorophenyl)-N-[1-cyclopropyl-2,2,2-trifluoroethyl]-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP1, 30 mg (75 μmol) of the compound from Example 64A werereacted with 19.8 mg (11.3 μmol) ofrac-1-cyclopropyl-2,2,2-trifluoroethanamine hydrochloride in thepresence of 29 mg (75 μmol) of HATU and 39 μl (0.23 mmol) ofN,N-diisopropylethylamine in 0.77 ml of dimethylformamide. The mixturewas diluted with 1 ml of acetonitrile and 0.5 ml of water and thesolution was purified by means of preparative HPLC (column: ChromatorexC18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05% formic acid gradient;0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrile and for afurther 3 min 90% acetonitrile). 25.8 mg (65% of theory, 99% purity) ofthe title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.30-0.40 (m, 1H), 0.50-0.71 (m, 3H),1.18-1.29 (m, 1H), 2.31-2.39 (m, 1H), 2.86-2.97 (m, 1H), 3.33-3.41 (m,1H), 3.52-3.61 (m, 1H), 4.20-4.26 (m, 1H), 4.35-4.47 (m, 1H), 5.31 (dd.1H), 7.58-7.70 (m, 2H), 7.76-7.83 (m, 2H), 8.51 (dd, 1H), 8.70-8.75 (m,2H), 10.38 (dd, 1H).

LC-MS (Method 1): R_(t)=1.02 min; 521 [M+H]⁺.

Example 2807-[3-Hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP2, 150 mg (323 μmol) of the compound from Example 100Cwere reacted with 32.7 mg (323 μmol) of 3-hydroxypyrrolidin-2-one (CAS:15166-68-4) in the presence of 67.1 mg (485 μmol) of potassiumcarbonate, 13 mg (58 μmol) of palladium(II) acetate and 67.4 mg (116μmol) of Xantphos in 2.97 ml of 1,4-dioxane. Subsequently, the volume ofthe mixture was reduced under reduced pressure and it was diluted with 3ml of acetonitrile and 1 ml of aqueous hydrochloric acid, filtered andpurified by means of preparative HPLC (column: Chromatorex C18, 10 μm,125×30 mm, solvent: acetonitrile/0.05% formic acid gradient; (0 to 3min. 10% acetonitrile to 35 min. 90% acetonitrile and a further 3 min.90% acetonitrile), and 118.4 mg (69% of theory, 99% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.11 (d, 1H), 9.08 (s, 1H), 8.74 (d,1H), 8.55 (d, 1H), 7.64-7.56 (m, 2H), 5.91 (d, 1H), 4.83-4.71 (m, 1H),4.43-4.35 (m, 1H), 3.62-3.54 (m, 1H), 3.38-3.32 (m, 1H), 2.36-2.27 (m,1H), 1.95-1.60 (m, 3H), 0.98 (t, 3H).

LC-MS (Method 1): R_(t)=1.00 min; 529 [M+H]⁺.

110 mg of the title compound (diastereomer mixture) were separated intothe diastereomers by chiral HPLC (preparative HPLC: column: DaicelChiralcel OZ-H 5 μm 250×20 mm; eluent: 20% ethanol, 80% isohexane;temperature: 23° C.; flow rate: 20 ml/min; UV detection: 220 nm).

This gave (in the sequence of elution from the column) 41.4 mg ofdiastereomer 1 (100% de) R_(t)=2.27 min and 44.8 mg (93% de) ofdiastereomer 2 R_(t)=2.67 min.

[Analytical HPLC: column: Chiralcel OZ-3 3 μm; eluent: 20% ethanol, 80%isohexane; flow rate: 1.0 ml/min; UV detection: 220 nm].

Diastereomer 1 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90%acetonitrile and a further 3 min. 90% acetonitrile)), and 37.0 mg (22%of theory, 99% purity) of the title compound from Example 281 wereobtained.

Diastereomer 2 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90%acetonitrile and a further 3 min. 90% acetonitrile)), and 39.8 mg (23%of theory, 99% purity) of the title compound from Example 282 wereobtained.

Example 2817-[3-Hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.11 (d, 1H), 9.08 (s, 1H), 8.74 (d,1H), 8.55 (d, 1H), 7.64-7.56 (m, 2H), 5.91 (d, 1H), 4.82-4.72 (m, 1H),4.43-4.35 (m, 1H), 3.62-3.54 (m, 1H), 3.38-3.32 (m, 1H), 2.37-2.27 (m,1H), 1.97-1.61 (m, 3H), 0.98 (t, 3H).

LC-MS (Method 3): R_(t)=1.89 min; 529 [M+H]⁺.

Example 2827-[3-Hydroxy-2-oxopyrrolidin-1-yl-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-4-oxo-N-trifluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.11 (d, 1H), 9.08 (s, 1H), 8.74 (d,1H), 8.55 (d, 1H), 7.64-7.56 (m, 2H), 5.91 (d, 1H), 4.84-4.70 (m, 1H),4.43-4.35 (m, 1H), 3.62-3.53 (m, 1H), 3.38-3.32 (m, 1H), 2.36-2.26 (m,1H), 1.96-1.60 (m, 3H), 0.98 (t, 3H).

LC-MS (Method 3): R_(t)=1.89 min; 529 [M+H]⁺.

Example 283N-[(1-Cyclopropyl-2,2,2-trifluoroethyl]-1-(2,4-difluorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP2, 560 mg (1.22 mmol) of the compound from Example 101Awere reacted with 124 mg (1.22 mmol) of (4S)-4-hydroxypyrrolidin-2-one(CAS: 68108-18-9) in the presence of 254 mg (1.84 mmol) of potassiumcarbonate, 49.4 mg (220 μmol) of palladium(II) acetate and 255 mg (440μmol) of Xantphos in 11.2 ml of 1,4-dioxane. Subsequently, the volume ofthe mixture was reduced under reduced pressure, and the residue wasacidified with 1N aqueous hydrochloric acid and dichloromethane. Thecrude product was purified by means of normal phase chromatography(cyclohexane-ethyl acetate gradient), and 316 mg (49% of theory; 99%purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.36 (d, 1H), 8.84 (s, 1H), 8.71 (d,1H), 8.52 (dd, 1H), 7.92-7.82 (m, 1H), 7.66-7.59 (m, 1H), 7.41-7.33 (m,1H), 5.32 (dd, 1H), 4.48-4.35 (m, 1H), 4.31-4.26 (m, 1H), 3.72-3.61 (m,1H), 3.52-3.42 (m, 1H), 3.00-2.87 (m, 1H), 2.42-2.32 (m, 1H), 1.29-1.19(m, 1H), 0.71-0.50 (m, 3H), 0.39-0.30 (m, 1H).

LC-MS (Method 1): R_(t)=1.06 min; 523 [M+H]⁺.

310 mg of the title compound (diastereomer mixture) were separated intothe diastereomers by chiral HPLC (preparative HPLC: column: DaicelChiralpak IE 5 m 250×20 mm; eluent: 50% ethanol, 50% isohexane;temperature: 25° C.; flow rate: 15 ml/min; UV detection: 210 nm).

This gave (in the sequence of elution from the column) 145 mg ofdiastereomer 1 (100% de) R_(t)=2.95 min and 128 mg (100% de) ofdiastereomer 2 R_(t)=5.61 min.

[Analytical HPLC: column: Chiraltek IE-3 3 μm; eluent: 50% ethanol, 50%isohexane; UV detection: 220 nm].

Diastereomer 1 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90%acetonitrile and a further 3 min. 90% acetonitrile)), and 129.7 mg (20%of theory, 99% purity) of the title compound from Example 284 wereobtained.

Diastereomer 2 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90%acetonitrile and a further 3 min. 90% acetonitrile)), and 112 mg (17% oftheory, 99% purity) of the title compound from Example 271 wereobtained.

Example 284 N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-1-(2,4-difluorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.11 (d, 1H), 9.08 (s, 1H), 8.74 (d,1H), 8.55 (d, 1H), 7.64-7.56 (m, 2H), 5.91 (d, 1H), 4.84-4.70 (m, 1H),4.43-4.35 (m, 1H), 3.62-3.53 (m, 1H), 3.38-3.32 (m, 1H), 2.36-2.26 (m,1H), 1.96-1.60 (m, 3H), 0.98 (t, 3H).

LC-MS (Method 3): R_(t)=1.89 min; 529 [M+H]⁺.

Example 2851-(2,4-Difluorophenyl)-7-[(4R)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 140 mg (314 μmol) of the compound from Example 68Awere reacted with 38.1 mg (377 μmol) of (4R)-4-hydroxypyrrolidin-2-one(CAS: 22677-21-0) in the presence of 65.1 mg (471 μmol) of potassiumcarbonate, 7.1 mg (31 μmol) of palladium(II) acetate and 18 mg (31 μmol)of Xantphos in 3.1 ml of 1,4-dioxane. After a reaction at 80° C.overnight, another 0.1 eq. of palladium(II) acetate and 0.1 eq. ofXantphos were added and the mixture was stirred for a further 3 h.Subsequently, the volume of the mixture was concentrated under reducedpressure, the residue was taken up with 0.5 ml of water and 3 ml ofacetonitrile and filtered, and the crude product was separated by meansof preparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm, eluent:acetonitrile/0.05% formic acid gradient (0 to 3 min 10% acetonitrile, to35 min to 90% acetonitrile and for a further 3 min 90% acetonitrile)).63.2 mg (39% of theory, 100% purity) of the title compound wereobtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.22 (d, 1H), 8.87-8.83 (m, 1H),8.71 (d, 1H), 8.52 (dd, 1H), 7.92-7.83 (m, 1H), 7.67-7.58 (m, 1H),7.41-7.33 (m, 1H), 5.32 (dd, 1H), 4.84-4.70 (m, 1H), 4.32-4.24 (m, 1H),3.72-3.61 (m, 1H), 3.52-3.42 (m, 1H), 3.00 (m, 1H), 2.41-2.31 (m, 1H),1.96-1.83 (m, 1H), 1.73-1.59 (m, 1H), 0.98 (t, 3H).

LC-MS (Method 3): R_(t)=1.83 min; 511 [M+H]⁺.

Example 2861-(2,4-Difluorophenyl)-4-oxo-7-(2-oxo-2,5-dihydro-1H-pyrrol-1-yl)-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

To a solution of 47 mg (92 μmol) of the compound from Example 285 in 737μl of toluene were added 40 mg (74 μmol) of tetrabutylammoniumtriphenyldifluorosilicate and 40.0 μl (230 μmol) ofdiisopropylethylamine. The mixture was stirred at room temperature for afurther 5 min and then 61.2 mg (203 μmol) of perfluorobutane-1-sulphonylfluoride were added. The mixture was stirred at room temperature for afurther 20 min and then all volatile constituents were removed underreduced pressure. The residue was stirred with 4 ml of acetonitrile and2 ml of water. The precipitate was filtered off with suction and driedunder high vacuum. 19.6 mg (37% of theory, 85% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.22 (d, 1H), 8.85 (s, 1H), 8.73 (d,1H), 8.53 (d, 1H), 7.93-7.84 (m, 1H), 7.64-7.58 (m, 1H), 7.53 (d, 1H),7.41-7.31 (m, 1H), 6.29 (d, 1H), 4.82-4.71 (m, 1H), 4.24 (s, 2H),1.96-1.84 (m, 1H), 1.72-1.61 (m, 1H), 0.98 (t, 3H).

LC-MS (Method 3): R_(t)=2.13 min; 493 [M+H]⁺.

Example 287N-[1-(2-Chlorophenyl)-2,2,2-trifluoroethyl]-1-(2-fluorophenyl)-7-[3-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Racemic Diastereomer Mixture)

According to GP1, 75.0 mg (196 μmol) of the compound from Example 33Bwere reacted with 61.5 mg (293 μmol) ofrac-1-(2-chlorophenyl)-2,2,2-trifluoroethanamine in the presence of 74.4mg (196 μmol) of HATU and 102 μl (587 μmol) of N,N-diisopropylethylaminein 2 ml of dimethylformamide. The mixture was diluted with 1 ml ofacetonitrile and 0.5 ml of water and the solution was purified by meansof preparative HPLC (column: Chromatorex C18, 10 m, 125×30 mm, solvent:acetonitrile/0.05% formic acid gradient; 0 to 3 min 10% acetonitrile, to35 min 90% acetonitrile and for a further 3 min 90% acetonitrile). 94.5mg (83% of theory, 99% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.33 (d, 1H), 8.84 (s, 1H), 8.78 (d,1H), 8.58-8.52 (m, 1H), 7.82-7.41 (m, 8H), 6.53-6.43 (m, 1H), 5.90 (d,1H), 4.45-4.32 (m, 1H), 3.60-3.46 (m, 1H), 3.36-3.20 (m, 1H partiallyunder the water signal), 2.34-2.24 (m, 1H), 1.83-1.66 (m, 1H).

LC-MS (Method 3): R_(t)=2.11 min; 575 [M+H]⁺.

90 mg of the title compound (diastereomer mixture) were separated intothe diastereomers by two chiral HPLC operations (preparative HPLC:column: Daicel Chiralcel OX-H 5 m 250×20 mm; eluent: 100% ethanol,temperature: 45° C.; flow rate: 15 ml/min; UV detection: 220 nm, andcolumn: Daicel Chiralpak IF m 250×20 mm; eluent: 35% ethanol, 65%isohexane, temperature: 45° C.; flow rate: 15 ml/min; UV detection: 220nm).

This gave (in the sequence of elution from the column) 12 mg (enantiomer1 of diastereomer 1, (93% de) R_(t)=6.29 min, 15 mg (enantiomer 1 ofdiastereomer 2, 100% de) R_(t)=6.93 min, 15 mg (enantiomer 2 ofdiastereomer 2, 80% de) R_(t)=10.88 min, and 19 mg (enantiomer 2 ofdiastereomer 1, 100% de) R_(t)=13.11 min.

[Analytical HPLC: column: Chiralcel OX-H 5 m 250×4.6 mm; eluent: 100%ethanol; flow rate: 1 ml/min; temperature: 45° C.; UV detection: 220 nm]

Enantiomer 1 of diastereomer 1 was additionally purified by means ofpreparative HPLC (column: Chromatorex C18, 10 m, 125×30 mm, solvent:acetonitrile/0.05% formic acid gradient; (0 to 3 min. 10% acetonitrileto 35 min. 90% acetonitrile and a further 3 min. 90% acetonitrile)), and11.3 mg (10% of theory, 99% purity) of the title compound from Example288 were obtained.

Enantiomer 1 of diastereomer 2 was additionally purified by means ofpreparative HPLC (column: Chromatorex C18, 10 m, 125×30 mm, solvent:acetonitrile/0.05% formic acid gradient; (0 to 3 min. 10% acetonitrileto 35 min. 90% acetonitrile and a further 3 min. 90% acetonitrile)), and12.8 mg (11% of theory, 99% purity) of the title compound from Example289 were obtained.

Enantiomer 2 of diastereomer 2 was additionally purified by means ofpreparative HPLC (column: Chromatorex C18, 10 m, 125×30 mm, solvent:acetonitrile/0.05% formic acid gradient; (0 to 3 min. 10% acetonitrileto 35 min. 90% acetonitrile and a further 3 min. 90% acetonitrile)), and14.2 mg (13% of theory, 99% purity) of the title compound from Example290 were obtained.

Enantiomer 2 of diastereomer 1 was additionally purified by means ofpreparative HPLC (column: Chromatorex C18, 10 m, 125×30 mm, solvent:acetonitrile/0.05% formic acid gradient; (0 to 3 min. 10% acetonitrileto 35 min. 90% acetonitrile and a further 3 min. 90% acetonitrile)), and15.7 mg (14% of theory, 99% purity) of the title compound from Example291 were obtained.

Example 288

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.33 (d, 1H), 8.84 (s, 1H), 8.78 (d,1H), 8.57-8.57 (m, 1H), 7.82-7.40 (m, 8H), 6.52-6.42 (m, 1H), 5.90 (d,1H), 4.43-4.32 (m, 1H), 3.60-3.46 (m, 1H), 3.34-3.20 (m, 1H partiallyunder the water signal), 2.34-2.24 (m, 1H), 1.83-1.66 (m, 1H).

LC-MS (Method 3): R_(t)=2.11 min; 575 [M+H]⁺.

Example 289

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.33 (d, 1H), 8.84 (s, 1H), 8.78 (d,1H), 8.57-8.51 (m, 1H), 7.81-7.42 (m, 8H), 6.53-6.42 (m, 1H), 5.90 (d,1H), 4.44-4.31 (m, 1H), 3.59-3.45 (m, 1H), 3.36-3.19 (m, 1H partiallyunder the water signal), 2.33-2.23 (m, 1H), 1.83-1.65 (m, 1H).

LC-MS (Method 3): R_(t)=2.14 min; 575 [M+H]⁺.

Example 290

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.33 (d, 1H), 8.84 (s, 1H), 8.78 (d,1H), 8.57-8.51 (m, 1H), 7.81-7.41 (m, 8H), 6.53-6.42 (m, 1H), 5.90 (d,1H), 4.44-4.31 (m, 1H), 3.58-3.46 (m, 1H), 2.34-2.23 (m, 1H), 1.82-1.66(m, 1H). One proton resonance under the water signal.

LC-MS (Method 3): R_(t)=2.11 min; 575 [M+H]⁺.

Example 291

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.33 (d, 1H), 8.84 (s, 1H), 8.78 (d,1H), 8.58-8.52 (m, 1H), 7.82-7.40 (m, 8H), 6.53-6.42 (m, 1H), 5.90 (d,1H), 4.45-4.32 (m, 1H), 3.60-3.45 (m, 1H), 3.35-3.19 (m, 1H partiallyunder the water signal), 2.34-2.23 (m, 1H), 1.82-1.67 (m, 1H).

LC-MS (Method 3): R_(t)=2.11 min; 575 [M+H]⁺.

Example 2921-(2,6-Difluorophenyl)-7-[3-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP2, 150 mg (336 μmol) of the compound from Example 86Awere reacted with 34.0 mg (336 μmol) of 3-hydroxypyrrolidin-2-one (CAS:15166-68-4) in the presence of 69.8 mg (505 μmol) of potassiumcarbonate, 14 mg (61 μmol) of palladium(II) acetate and 70.1 mg (121μmol) of Xantphos in 3.09 ml of 1,4-dioxane. Subsequently, the volume ofthe mixture was reduced under reduced pressure and it was diluted with 3ml of acetonitrile and acidified with 1 ml of water, filtered andpurified by means of preparative HPLC (column: Chromatorex C18, 10 m,125×30 mm, solvent: acetonitrile/0.05% formic acid gradient; (0 to 3min. 10% acetonitrile to 35 min. 90% acetonitrile and a further 3 min.90% acetonitrile), and 127.3 mg (73% of theory, 99% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.12 (d, 1H), 9.03 (s, 1H), 8.74 (d,1H), 8.55 (d, 1H), 7.79-7.70 (m, 1H), 7.49-7.41 (m, 2H), 5.90 (d, 1H),4.83-4.71 (m, 1H), 4.42-4.34 (m, 1H), 3.55-3.49 (m, 1H), 3.33-3.23 (m,1H partially under the water signal), 2.34-2.23 (m, 1H), 1.95-1.61 (m,3H), 0.98 (t, 3H).

LC-MS (Method 3): R_(t)=1.87 min; 511 [M+H]⁺.

120 mg of the title compound (diastereomer mixture) were separated intothe diastereomers by chiral HPLC (preparative HPLC: column: DaicelChiralcel OX-H 5 m 250×45 mm; eluent: 20% ethanol, 55% isohexane;temperature: 23° C.; flow rate: 20 ml/min; UV detection: 220 nm).

This gave (in the sequence of elution from the column) 52.5 mg ofdiastereomer 1 (100% de) R_(t)=1.13 min and 45.5 mg (94% de) ofdiastereomer 2 R_(t)=1.25 min.

[Analytical HPLC: column: Daicel Chiralpak OX-3 3 m 50×4.6 mm; eluent:50% ethanol, 50% isohexane; flow rate: 1 ml/min; UV detection: 220 nm].

Diastereomer 1 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90%acetonitrile and a further 3 min. 90% acetonitrile)), and 40.7 mg (23%of theory, 99% purity) of the title compound from Example 293 wereobtained.

Diastereomer 2 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90%acetonitrile and a further 3 min. 90% acetonitrile)), and 41.1 mg (24%of theory, 99% purity) of the title compound from Example 294 wereobtained.

Example 293

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.12 (d, 1H), 9.03 (s, 1H), 8.74 (d,1H), 8.55 (d, 1H), 7.79-7.70 (m, 1H), 7.50-7.41 (m, 2H), 5.90 (d, 1H),4.84-4.70 (m, 1H), 4.43-4.34 (m, 1H), 3.56-3.48 (m, 1H), 3.34-3.24 (m,1H partially under the water signal), 2.33-2.23 (m, 1H), 1.96-1.61 (m,3H), 0.98 (t, 3H).

LC-MS (Method 1): R_(t)=0.98 min; 511 [M+H]⁺.

Example 294

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.13 (d, 1H), 9.03 (s, 1H), 8.74 (d,1H), 8.55 (d, 1H), 7.79-7.70 (m, 1H), 7.50-7.41 (m, 2H), 5.91 (d, 1H),4.84-4.70 (m, 1H), 4.43-4.34 (m, 1H), 3.56-3.47 (m, 1H), 3.33-3.24 (m,1H partially under the water signal), 2.34-2.23 (m, 1H), 1.96-1.60 (m,3H), 0.99 (t, 3H).

LC-MS (Method 1): R_(t)=0.98 min; 511 [M+H]⁺.

Example 295N-[1-Cyclopropyl-2,2,2-trifluoroethyl]-1-(2,6-difluorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP2, 100 mg (218 μmol) of the compound from Example 102Awere reacted with 22.1 mg (218 μmol) of (4S)-4-hydroxypyrrolidin-2-one(CAS: 68108-18-9) in the presence of 45.3 mg (328 μmol) of potassiumcarbonate, 8.8 mg (39 μmol) of palladium(II) acetate and 46 mg (79 μmol)of Xantphos in 2 ml of 1,4-dioxane. Subsequently, the volume of themixture was concentrated under reduced pressure, the residue wasacidified with 1N aqueous hydrochloric acid, diluted with 5 ml ofacetonitrile and filtered, and the crude product was purified by meansof preparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm, solvent:acetonitrile/0.05% formic acid gradient (0 to 3 min 10% acetonitrile, to35 min to 90% acetonitrile and for a further 3 min 90% acetonitrile)).68.9 mg (60% of theory, 99% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.28 (d, 1H), 9.02 (s, 1H), 8.73 (d,1H), 8.54 (d, 1H), 7.81-7.72 (m, 1H), 7.50-7.42 (m, 2H), 5.33 (d, 1H),4.47-4.34 (m, 1H), 4.29-4.22 (m, 1H), 3.64 (dd, 1H), 3.43 (d, 1H), 2.93(dd, 1H), 2.37 (d, 1H), 1.29-1.18 (m, 1H), 0.71-0.51 (m, 3H), 0.40-0.31(m, 1H).

LC-MS (Method 1): R_(t)=1.05 min; 523 [M+H]⁺.

65 mg of the title compound (diastereomer mixture) were separated intothe diastereomers by chiral HPLC (preparative HPLC: column: DaicelChiralcel OX-H 250×20 mm; eluent: 30% ethanol, 70% isohexane;temperature: 23° C.; flow rate: 20 ml/min; UV detection: 220 nm).

This gave (in the sequence of elution from the column) 17.3 mg ofdiastereomer 1 (100% de) R_(t)=2.16 min and 17.9 mg (100% de) ofdiastereomer 2 R_(t)=3.39 min.

[Analytical HPLC: column: Daicel Chiralpak OX-3 3 m 50×4.6 mm; eluent:20% ethanol, 80% isohexane; flow rate: 1 ml/min; temperature: 30° C.; UVdetection: 220 nm].

Diastereomer 1 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90%acetonitrile and a further 3 min. 90% acetonitrile)), and 16.9 mg (15%of theory, 99% purity) of the title compound from Example 296 wereobtained.

Diastereomer 2 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90%acetonitrile and a further 3 min. 90% acetonitrile)), and 17.7 mg (15%of theory, 99% purity) of the title compound from Example 297 wereobtained.

Example 296N-[(1R)-1-cyclopropyl-2,2,2-trifluoroethyl]-1-(2,6-difluorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.27 (d, 1H), 9.02 (s, 1H), 8.73 (d,1H), 8.54 (d, 1H), 7.80-7.71 (m, 1H), 7.50-7.42 (m, 2H), 5.33 (d, 1H),4.46-4.36 (m, 1H), 4.29-4.23 (m, 1H), 3.64 (dd, 1H), 3.43 (d, 1H), 2.93(dd, 1H), 2.37 (d, 1H), 1.28-1.19 (m, 1H), 0.71-0.52 (m, 3H), 0.40-0.31(m, 1H).

LC-MS (Method 3): R_(t)=1.84 min; 523 [M+H]⁺.

Alternatively, the title compound can also be obtained according to GP2by reacting the compound from Example 103A with(4S)-4-hydroxypyrrolidin-2-one (CAS: 68108-18-9).

Example 297 N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-1-(2,6-difluorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.28 (d, 1H), 9.02 (s, 1H), 8.73 (d,1H), 8.54 (d, 1H), 7.81-7.71 (m, 1H), 7.50-7.41 (m, 2H), 5.33 (d, 1H),4.47-4.34 (m, 1H), 4.29-4.22 (m, 1H), 3.64 (dd, 1H), 3.43 (d, 1H), 2.93(dd, 1H), 2.37 (d, 1H), 1.30-1.18 (m, 1H), 0.71-0.51 (m, 3H), 0.39-0.30(m, 1H).

LC-MS (Method 3): R_(t)=1.84 min; 523 [M+H]⁺.

Alternatively, the title compound can also be obtained according to GP2by reacting the compound from Example 104A with(4S)-4-hydroxypyrrolidin-2-one (CAS: 68108-18-9).

Example 298N-[1-(2-Chlorophenyl)-2,2,2-trifluoroethyl]-1-(2,4-difluorophenyl)-7-[(3S)-3-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP2, 439 mg (798 μmol, 96% purity) of the compound fromExample 73A were reacted with 99.8 mg (957 μmol) of(3S)-3-hydroxypyrrolidin-2-one (CAS: 34368-52-0) in the presence of 132mg (957 μmol) of potassium carbonate, 18 mg (80 μmol) of palladium(II)acetate and 92.3 mg (160 μmol) of Xantphos in 79 ml of 1,4-dioxane.Subsequently, the mixture was admixed with 50 ml of water and extractedthree times with 30 ml of ethyl acetate. The aqueous phase was acidifiedwith 1N aqueous hydrochloric acid and extracted again with ethylacetate. The combined organic phases were washed with saturated aqueoussodium chloride solution, dried over magnesium sulphate, filtered andpurified by means of normal phase chromatography (cyclohexane-ethylacetate gradient). 280 mg (59% of theory, 100% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.32 (d, 1H), 8.87 (s, 1H), 8.78 (d,1H), 8.54 (dd, 1H), 7.92-7.77 (m, 1H), 7.68-7.48 (m, 5H), 7.40-7.31 (m,1H), 6.53-6.42 (m, 1H), 5.91 (d, 1H), 4.45-4.33 (m, 1H), 3.63-3.50 (m,1H), 2.36-2.26 (m, 1H), 1.83-1.67 (m, 1H).

LC-MS (Method 1): R_(t)=1.20 min; 593 [M+H]⁺.

Example 299N-[1-(2-Chlorophenyl)-2,2,2-trifluoroethyl]-1-(2,4-difluorophenyl)-7-[(3R)-3-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP2, 606 mg (987 μmol, 86% purity) of the compound fromExample 73A were reacted with 123 mg (1.18 mmol) of(3R)-3-hydroxypyrrolidin-2-one (CAS: 77510-50-0) in the presence of 164mg (1.18 mmol) of potassium carbonate, 22 mg (99 μmol) of palladium(II)acetate and 114 mg (197 μmol) of Xantphos in 99 ml of 1,4-dioxane. Afterreaction overnight, a further 0.1 eq. of palladium(II) acetate and 0.2eq. of Xantphos were added and the mixture was stirred at 80° C. for 2.5h. Subsequently, the mixture was admixed with 50 ml of water, acidifiedwith 1N aqueous hydrochloric acid and extracted three times with 30 mlof ethyl acetate. The combined organic phases were washed with saturatedaqueous sodium chloride solution, dried over magnesium sulphate,filtered and purified by means of normal phase chromatography(cyclohexane-ethyl acetate gradient). 284 mg (49% of theory, 100%purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.32 (d, 1H), 8.87 (s, 1H), 8.77 (d,1H), 8.54 (dd, 1H), 7.92-7.76 (m, 1H), 7.67-7.47 (m, 5H), 7.40-7.30 (m,1H), 6.53-6.41 (m, 1H), 5.91 (d, 1H), 4.45-4.32 (m, 1H), 3.62-3.49 (m,1H), 2.35-2.27 (m, 1H), 1.84-1.68 (m, 1H).

LC-MS (Method 4): R_(t)=3.69 min; 593 [M+H]⁺.

Example 3001-(2,4-Difluorophenyl)-N-[1-(2,6-difluorophenyl)-2,2,2-trifluoroethyl]-7-[(3R)-3-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP2, 428 mg (719 μmol, 89% purity) of the compound fromExample 80A were reacted with 89.9 mg (863 μmol) of(3R)-3-hydroxypyrrolidin-2-one (CAS: 77510-50-0) in the presence of 123mg (863 μmol) of potassium carbonate, 16 mg (72 μmol) of palladium(II)acetate and 83.2 mg (144 μmol) of Xantphos in 72 ml of 1,4-dioxane.Subsequently, the mixture was admixed with 50 ml of water, acidifiedwith 1N aqueous hydrochloric acid and extracted three times with 30 mlof ethyl acetate. The combined organic phases were washed with saturatedaqueous sodium chloride solution, dried over magnesium sulphate,filtered and purified by means of normal phase chromatography(cyclohexane-ethyl acetate gradient). 266 mg (62% of theory, 100%purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.36 (d, 1H), 8.89 (s, 1H), 8.77 (d,1H), 8.56-8.50 (m, 1H), 7.93-7.74 (m, 1H), 7.68-7.57 (m, 2H), 7.40-7.28(m, 3H), 6.50-6.39 (m, 1H), 5.91 (d, 1H), 4.45-4.32 (m, 1H), 3.62-3.50(m, 1H), 2.36-2.27 (m, 1H), 1.84-1.70 (m, 1H).

LC-MS (Method 1): R_(t)=1.08 min; 595 [M+H]⁺.

Example 3011-(2,4-Difluorophenyl)-7-[4-methyl-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP2, 200 mg (449 μmol) of the compound from Example 67Awere reacted with 49.2 mg (471 μmol) of 4-methyl-2-pyrrolidinone(racemate) in the presence of 93.0 mg (673 μmol) of potassium carbonate,18 mg (81 μmol) of palladium(II) acetate and 93.5 mg (162 μmol) ofXantphos in 4 ml of 1,4-dioxane. Subsequently, the volume of the mixturewas concentrated under reduced pressure, and the residue was taken upwith 2 ml of 1N aqueous hydrochloric acid and 8 ml of acetonitrile andpurified by means of preparative HPLC (column: Chromatorex C18, 10 μm,125×30 mm, solvent: acetonitrile/0.05% formic acid gradient; 0 to 3 min10% acetonitrile, to 35 min 90% acetonitrile and for a further 3 min 90%acetonitrile). 92.9 mg (40% of theory, 99% purity) of the title compoundwere obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.22 (d, 1H), 8.85 (s, 1H), 8.70 (d,1H), 8.49 (d, 1H), 7.92-7.82 (m, 1H), 7.68-7.59 (m, 1H), 7.40-7.33 (m,1H), 4.84-4.70 (m, 1H), 3.76-3.65 (m, 1H), 3.18-3.06 (m, 1H), 2.79-2.65(m, 1H), 2.46-2.23 (m, 2H), 1.95-1.83 (m, 1H), 1.73-1.59 (m, 1H),1.06-0.94 (m, 6H).

LC-MS (Method 1): R_(t)=1.19 min; 509 [M+H]⁺.

89 mg of the title compound (diastereomer mixture) were separated intothe diastereomers by chiral HPLC (preparative HPLC: column: DaicelChiralpak AZ-H 5 μm 250×20 mm; eluent: 25% ethanol, 75% isohexane;temperature: 25° C.; flow rate: 20.2 ml/min; UV detection: 265 nm).

This gave (in the sequence of elution from the column) 45.4 mg ofdiastereomer 1 (100% de) R_(t)=3.42 min and 37.1 mg (100% de) ofdiastereomer 2 R_(t)=3.93 min.

[Analytical HPLC: column: Daicel Chiralpak AZ-3 3 μm 50×4.6 mm; eluent:20% ethanol, 80% isohexane; flow rate: 1 ml/min; UV detection: 220 nm].

Diastereomer 1 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90%acetonitrile and a further 3 min. 90% acetonitrile)), and 33.6 mg (15%of theory, 99% purity) of the title compound from Example 302 wereobtained.

Diastereomer 2 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90%acetonitrile and a further 3 min. 90% acetonitrile)), and 26.9 mg (12%of theory, 99% purity) of the title compound from Example 303 wereobtained.

Example 3021-(2,4-Difluorophenyl)-7-[4-methyl-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.22 (d, 1H), 8.85 (s, 1H), 8.70 (d,1H), 8.49 (d, 1H), 7.92-7.83 (m, 1H), 7.68-7.59 (m, 1H), 7.41-7.33 (m,1H), 4.84-4.70 (m, 1H), 3.76-3.65 (m, 1H), 3.18-3.06 (m, 1H), 2.78-2.65(m, 1H), 2.46-2.23 (m, 2H), 1.96-1.83 (m, 1H), 1.73-1.60 (m, 1H),1.07-0.94 (m, 6H).

LC-MS (Method 3): R_(t)=2.27 min; 509 [M+H]⁺.

Example 3031-(2,4-Difluorophenyl)-7-[4-methyl-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.22 (d, 1H), 8.85 (s, 1H), 8.70 (d,1H), 8.49 (d, 1H), 7.92-7.82 (m, 1H), 7.68-7.59 (m, 1H), 7.41-7.32 (m,1H), 4.83-4.70 (m, 1H), 3.77-3.64 (m, 1H), 3.18-3.07 (m, 1H), 2.78-2.65(m, 1H), 2.46-2.22 (m, 2H), 1.96-1.84 (m, 1H), 1.73-1.59 (m, 1H),1.06-0.93 (m, 6H).

LC-MS (Method 3): R_(t)=2.27 min; 509 [M+H]⁺.

Example 3041-(2,6-Difluorophenyl)-7-[1-hydroxy-3-azabicyclo[3.1.0]hex-3-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP3, 240 mg (538 μmol) of the compound from Example 86Awere reacted with 80.7 mg (565 μmol) of 3-azabicyclo[3.1.0]hexan-1-olhydrochloride (racemate, 95% purity) and 328 μl (1.88 mmol) ofN,N-diisopropylethylamine in 2.4 ml of dimethylformamide. The crudeproduct was diluted with 0.5 ml of acetonitrile and 0.5 ml of 1N aqueoushydrochloric acid and purified by means of preparative HPLC (column:Chromatorex C18, 10 m, 125×30 mm, solvent: acetonitrile/0.05% formicacid gradient; 0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrileand for a further 3 min 90% acetonitrile). 158.6 mg (57% of theory,98.7% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.41 (d, 1H), 8.76 (s, 1H), 8.29 (d,1H), 7.77-7.65 (m, 1H), 7.49-7.37 (m, 2H), 6.83-6.68 (m, 1H), 6.01 (d,1H), 4.81-4.67 (m, 1H), 3.94-3.83 (m, 0.5H), 3.72-3.60 (m, 0.5H),3.56-3.39 (m, 1.5H), 3.27-3.18 (m, 0.5H), 3.17-3.02 (m, 1H), 1.94-1.81(m, 1H), 1.71-1.47 (m, 2H), 1.07-0.92 (m, 4H), 0.48-0.37 (m, 1H).

LC-MS (Method 3): R_(t)=1.99 min; 509 [M+H]⁺.

150 mg of the title compound (diastereomer mixture) were separated intothe diastereomers by chiral HPLC (preparative HPLC: column: DaicelChiralcel OZ-H 5 m 250×20 mm; eluent: 20% ethanol, 80% isohexane;temperature: 23° C.; flow rate: 20 ml/min; UV detection: 220 nm).

This gave (in the sequence of elution from the column) 69.0 mg ofdiastereomer 1 (100% de) R_(t)=1.74 min and 50.9 mg (98% de) ofdiastereomer 2 R_(t)=2.48 min.

[Analytical HPLC: column: Daicel Chiralpak OX-3 3 m 50×4.6 mm; eluent:20% 2-propanol, 80% isohexane; flow rate: 1 ml/min; temperature: 30° C.;UV detection: 220 nm].

Diastereomer 1 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90%acetonitrile and a further 3 min. 90% acetonitrile)), and 48.6 mg (18%of theory, 99% purity) of the title compound from Example 305 wereobtained.

Diastereomer 2 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90%acetonitrile and a further 3 min. 90% acetonitrile)), and 41.5 mg (15%of theory, 99% purity) of the title compound from Example 306 wereobtained.

Example 3051-(2,6-Difluorophenyl)-7-[1-hydroxy-3-azabicyclo[3.1.0]hex-3-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.41 (d, 1H), 8.76 (s, 1H), 8.28 (d,1H), 7.77-7.65 (m, 1H), 7.49-7.36 (m, 2H), 6.84-6.69 (m, 1H), 6.00 (d,1H), 4.80-4.67 (m, 1H), 3.92-3.82 (m, 0.5H), 3.69-3.60 (m, 0.5H),3.56-3.39 (m, 1.5H), 3.16-3.02 (m, 1H), 1.94-1.82 (m, 1H), 1.71-1.48 (m,2H), 1.05-0.90 (m, 4H), 0.47-0.36 (m, 1H).

LC-MS (Method 3): R_(t)=1.96 min; 509 [M+H]⁺.

Example 3061-(2,6-Difluorophenyl)-7-[1-hydroxy-3-azabicyclo[3.1.0]hex-3-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.41 (d, 1H), 8.76 (s, 1H), 8.28 (d,1H), 7.77-7.65 (m, 1H), 7.48-7.36 (m, 2H), 6.83-6.68 (m, 1H), 6.00 (d,1H), 4.80-4.67 (m, 1H), 3.92-3.82 (m, 0.5H), 3.69-3.59 (m, 0.5H),3.54-3.39 (m, 1.5H), 3.16-3.02 (m, 1H), 1.94-1.81 (m, 1H), 1.71-1.47 (m,2H), 1.05-0.90 (m, 4H), 0.46-0.38 (m, 1H).

LC-MS (Method 3): R_(t)=1.96 min; 509 [M+H]⁺.

Example 3071-(2-Chloro-6-fluorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 100 mg (216 μmol) of the compound from Example 105Cwere reacted with 21.9 mg (216 μmol) of (S)-4-hydroxypyrrolidinone inthe presence of 44.8 mg (325 μmol) of potassium carbonate, 8.7 mg (39μmol) of palladium(II) acetate and 45 mg (78 μmol) of Xantphos in 1.98ml of 1,4-dioxane. Subsequently, the volume of the mixture wasconcentrated under reduced pressure, the residue was acidified with 1Naqueous hydrochloric acid and taken up with 3 ml of acetonitrile,filtered and purified by means of preparative HPLC (column: ChromatorexC18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05% formic acid gradient(0 to 3 min 10% acetonitrile, to 35 min to 90% acetonitrile and for afurther 3 min 90% acetonitrile)). 57.1 mg (50% of theory, 99% purity) ofthe title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.15 (d, 1H), 8.99 (s, 1H), 8.73 (d,1H), 8.54 (d, 1H), 7.78-7.56 (m, 3H), 5.32 (d, 1H), 4.82-4.71 (m, 1H),4.28-4.22 (m, 1H), 3.63-3.55 (m, 1H), 3.41-3.34 (m, 1H), 2.93 (dd, 1H),2.40-2.31 (m, 1H), 1.95-1.83 (m, 1H), 1.74-1.60 (m, 1H), 1.02-0.95 (m,3H).

LC-MS (Method 1): R_(t)=1.01 min; 527 [M+H]⁺.

Example 3081-(2-Chloro-6-fluorophenyl)-7-[(3R)-3-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 100 mg (216 μmol) of the compound from Example 105Cwere reacted with 21.9 mg (216 μmol) of (R)-3-hydroxypyrrolidinone inthe presence of 44.8 mg (325 μmol) of potassium carbonate, 8.7 mg (39μmol) of palladium(II) acetate and 45 mg (78 μmol) of Xantphos in 1.98ml of 1,4-dioxane. Subsequently, the volume of the mixture wasconcentrated under reduced pressure, the residue was acidified with 1Naqueous hydrochloric acid and taken up with 5 ml of acetonitrile,filtered and purified by means of preparative HPLC (column: ChromatorexC18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05% formic acid gradient(0 to 3 min 10% acetonitrile, to 35 min to 90% acetonitrile and for afurther 3 min 90% acetonitrile)). 57.5 mg (58% of theory, 99% purity) ofthe title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.17-10.11 (m, 1H), 9.00 (s, 1H),8.75 (d, 1H), 8.54 (d, 1H), 7.76-7.55 (m, 3H), 5.90 (d, 1H), 4.83-4.71(m, 1H), 4.41-4.33 (m, 1H), 3.51-3.42 (m, 1H), 3.27-3.18 (m, 1H),2.31-2.22 (m, 1H), 1.96-1.84 (m, 1H), 1.80-1.61 (m, 2H), 1.03-0.94 (m,1H).

LC-MS (Method 3): R_(t)=1.91 min; 527 [M+H]⁺.

Example 3091-(2-Chloro-6-fluorophenyl)-7-[(3S)-3-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 100 mg (216 μmol) of the compound from Example 105Cwere reacted with 21.9 mg (216 μmol) of (S)-3-hydroxypyrrolidinone inthe presence of 44.8 mg (325 μmol) of potassium carbonate, 8.7 mg (39μmol) of palladium(II) acetate and 45 mg (78 μmol) of Xantphos in 1.98ml of 1,4-dioxane. Subsequently, the volume of the mixture wasconcentrated under reduced pressure, the residue was acidified with 1Naqueous hydrochloric acid and taken up with 3 ml of acetonitrile,filtered and purified by means of preparative HPLC (column: ChromatorexC18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05% formic acid gradient(0 to 3 min 10% acetonitrile, to 35 min to 90% acetonitrile and for afurther 3 min 90% acetonitrile)). 63.3 mg (55% of theory, 99% purity) ofthe title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.14 (d, 1H), 9.00 (d, 1H), 8.75 (d,1H), 8.54 (d, 1H), 7.76-7.54 (m, 3H), 5.90 (d, 1H), 4.83-4.70 (m, 1H),4.42-4.33 (m, 1H), 3.52-3.41 (m, 1H), 3.28-3.18 (m, 1H), 2.32-2.23 (m,1H), 1.96-1.84 (m, 1H), 1.80-1.61 (m, 2H), 1.02-0.94 (m, 1H).

LC-MS (Method 3): R_(t)=1.91 min; 527 [M+H]⁺.

Example 3101-(2-Chloro-6-fluorophenyl)-7-[1-hydroxy-3-azabicyclo[3.1.0]hex-3-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP3, 100 mg (216 μmol) of the compound from Example 105Cwere reacted with 35.5 mg (238 μmol) of 3-azabicyclo[3.1.0]hexan-1-olhydrochloride (racemate, 91% purity) and 132 μl (757 μmol) ofN,N-diisopropylethylamine in 2 ml of dimethylformamide. The crudeproduct was diluted with 0.5 ml of acetonitrile and was purified bymeans of preparative HPLC (column: Chromatorex C18, 10 m, 125×30 mm,solvent: acetonitrile/0.05% formic acid gradient; 0 to 3 min 10%acetonitrile, to 35 min 90% acetonitrile and for a further 3 min 90%acetonitrile). 74.7 mg (66% of theory, 100% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.43 (d, 1H), 8.71 (s, 1H), 8.28 (d,1H), 7.75-7.50 (m, 3H), 6.83-6.69 (m, 1H), 5.99 (d, 1H), 4.80-4.67 (m,1H), 3.92-3.82 (m, 0.5H), 3.69-3.60 (m, 0.5H), 3.54-3.37 (m, 1.5H),3.24-2.97 (m, 1.5H), 1.94-1.82 (m, 1H), 1.72-1.46 (m, 2H), 1.05-0.92 (m,4H), 0.48-0.35 (m, 1H).

LC-MS (Method 3): R_(t)=2.04 min; 525 [M+H]⁺.

Example 3111-(2,6-Difluorophenyl)-7-[1-hydroxy-3-azabicyclo[3.1.0]hex-3-yl]-4-oxo-N-[(2S)-1,1,1-trifluoropropan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP3, 100 mg (232 μmol) of the compound from Example 106Awere reacted with 37.9 mg (255 μmol) of 3-azabicyclo[3.1.0]hexan-1-olhydrochloride (racemate, 91% purity) and 141 μl (811 μmol) ofN,N-diisopropylethylamine in 1 ml of dimethylformamide. The crudeproduct was diluted with 0.5 ml of acetonitrile and was purified bymeans of preparative HPLC (column: Chromatorex C18, 10 m, 125×30 mm,solvent: acetonitrile/0.05% formic acid gradient; 0 to 3 min 10%acetonitrile, to 35 min 90% acetonitrile and for a further 3 min 90%acetonitrile). 72.1 mg (63% of theory, 100% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.46 (d, 1H), 8.75 (s, 1H), 8.27 (d,1H), 7.77-7.65 (m, 1H), 7.48-7.36 (m, 2H), 6.83-6.69 (m, 1H), 6.00 (d,1H), 4.95-4.81 (m, 1H), 3.91-3.83 (m, 0.5H), 3.69-3.60 (m, 0.5H),3.55-3.38 (m, 1.5H), 3.26-3.02 (m, 1.5H), 1.69-1.47 (m, 1H), 1.37 (d,3H), 1.05-0.98 (m, 1H), 0.46-0.39 (m, 1H).

LC-MS (Method 3): R_(t)=1.89 min; 495 [M+H]⁺.

70 mg of the title compound (diastereomer mixture) were separated intothe diastereomers by chiral HPLC (preparative HPLC: column: DaicelChiralpak AZ-H 5 m 250×20 mm; eluent: 15% ethanol, 85% isohexane;temperature: 25° C.; flow rate: 20 ml/min; UV detection: 265 nm).

This gave (in the sequence of elution from the column) 34.4 mg ofdiastereomer 1 (100% de) R_(t)=2.29 min and 37.5 mg (100% de) ofdiastereomer 2 R_(t)=2.48 min.

[Analytical HPLC: column: Daicel Chiralpak AZ-3 3 μm 50×4.6 mm; eluent:10% ethanol, 90% isohexane; flow rate: 1 ml/min; UV detection: 220 nm].

Diastereomer 1 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90%acetonitrile and a further 3 min. 90% acetonitrile)), and 17.3 mg (15%of theory, 100% purity) of the title compound from Example 312 wereobtained.

Diastereomer 2 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90%acetonitrile and a further 3 min. 90% acetonitrile)), and 16.7 mg (15%of theory, 100% purity) of the title compound from Example 313 wereobtained.

Example 3121-(2,6-Difluorophenyl)-7-[1-hydroxy-3-azabicyclo[3.1.0]hex-3-yl]-4-oxo-N-[(2S)-1,1,1S-trifluoropropan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.46 (d, 1H), 8.75 (s, 1H), 8.27 (d,1H), 7.76-7.65 (m, 1H), 7.48-7.36 (m, 2H), 6.83-6.69 (m, 1H), 6.01 (d,1H), 4.93-4.83 (m, 1H), 3.91-3.83 (m, 0.5H), 3.69-3.60 (m, 0.5H),3.54-3.41 (m, 1.5H), 3.25-3.02 (m, 1.5H), 1.68-1.48 (m, 1H), 1.37 (d,3H), 1.04-0.98 (m, 1H), 0.46-0.39 (m, 1H).

LC-MS (Method 3): R_(t)=1.96 min; 495 [M+H]⁺.

Example 3131-(2,6-Difluorophenyl)-7-[1-hydroxy-3-azabicyclo[3.1.0]hex-3-yl]-4-oxo-N-[(2S)-1,1,1-trifluoropropan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.46 (d, 1H), 8.75 (s, 1H), 8.27 (d,1H), 7.76-7.65 (m, 1H), 7.47-7.37 (m, 2H), 6.81-6.69 (m, 1H), 6.00 (d,1H), 4.93-4.83 (m, 1H), 3.91-3.84 (m, 0.5H), 3.68-3.60 (m, 0.5H),3.53-3.41 (m, 1.5H), 3.25-3.04 (m, 1.5H), 1.68-1.48 (m, 1H), 1.37 (d,3H), 1.04-0.99 (m, 1H), 0.47-0.38 (m, 1H).

LC-MS (Method 3): R_(t)=1.88 min; 495 [M+H]⁺.

Example 3141-(2,4-Difluorophenyl)-7-[1-hydroxy-3-azabicyclo[3.1.0]hex-3-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=10.48 (d, 1H), 8.62 (s, 1H), 8.28 (d,1H), 7.85-7.75 (m, 1H), 7.65-7.53 (m, 1H), 7.38-7.28 (m, 1H), 6.81-6.66(m, 1H), 6.00 (d, 1H), 4.80-4.67 (m, 1H), 3.94-3.04 (m, 4H partiallyunder the water signal), 1.93-1.82 (m, 1H), 1.69-1.51 (m, 2H), 1.07-0.92(m, 4H), 0.48-0.35 (m, 1H).

LC-MS (Method 3): R_(t)=1.99 min; 509 [M+H]⁺.

Example 3151-(2,4-Difluorophenyl)-7-[1-hydroxy-3-azabicyclo[3.1.0]hex-3-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2)

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=10.48 (d, 1H), 8.62 (s, 1H), 8.28 (d,1H), 7.86-7.74 (m, 1H), 7.66-7.52 (m, 1H), 7.38-7.27 (m, 1H), 6.81-6.67(m, 1H), 6.00 (d, 1H), 4.80-4.67 (m, 1H), 3.93-3.06 (m, 4H partiallyunder the water signal), 1.93-1.81 (m, 1H), 1.71-1.50 (m, 2H), 1.06-0.91(m, 4H), 0.47-0.35 (m, 1H).

LC-MS (Method 3): R_(t)=1.99 min; 509 [M+H]⁺.

Example 3167-[1-Hydroxy-3-azabicyclo[3.1.0]hex-3-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-N-[(2S)-1,1,1-trifluoropropan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP3, 150 mg (334 μmol) of the compound from Example 107Awere reacted with 54.7 mg (367 μmol) of 3-azabicyclo[3.1.0]hexan-1-olhydrochloride (racemate, 91% purity) and 203 μl (1.17 mmol) ofN,N-diisopropylethylamine in 1.5 ml of dimethylformamide. The crudeproduct was diluted with 0.5 ml of acetonitrile and was purified bymeans of preparative HPLC (column: Chromatorex C18, 10 m, 125×30 mm,solvent: acetonitrile/0.05% formic acid gradient; 0 to 3 min 10%acetonitrile, to 35 min 90% acetonitrile and for a further 3 min 90%acetonitrile). 123.8 mg (72% of theory, 99% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.45 (d, 1H), 8.81 (s, 1H), 8.27 (d,1H), 7.64-7.50 (m, 2H), 6.83-6.68 (m, 1H), 6.02 (d, 1H), 4.95-4.82 (m,1H), 3.92-3.84 (m, 0.5H), 3.69-3.39 (m, 2H), 3.19-3.08 (m, 1H),1.69-1.50 (m, 1H), 1.37 (d, 3H), 1.06-0.98 (m, 1H), 0.48-0.39 (m, 1H).

LC-MS (Method 1): R_(t)=1.01 min; 513 [M+H]⁺.

120 mg of the title compound (diastereomer mixture) were separated intothe diastereomers by chiral SFC (preparative SFC: column: DaicelChiralpak IA 5 m 250×20 mm; eluent: 7% ethanol, 93% carbon dioxide;temperature: 40° C.; flow rate: 100 ml/min; UV detection: 210 nm).

This gave (in the sequence of elution from the column) 42.0 mg ofdiastereomer 1 (100% de) R_(t)=1.48 min and 47.2 mg (87% de) ofdiastereomer 2 R_(t)=1.57 min.

[Analytical SFC: column: Daicel Chiralpak IA; eluent: 10% ethanol, 90%carbon dioxide; flow rate: 3 ml/min; UV detection: 220 nm].

Diastereomer 1 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90%acetonitrile and a further 3 min. 90% acetonitrile)), and 26.9 mg (16%of theory, 100% purity) of the title compound from Example 317 wereobtained.

Diastereomer 2 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90%acetonitrile and a further 3 min. 90% acetonitrile)), and 38.8 mg (22%of theory, 100% purity) of the title compound from Example 318 wereobtained.

Example 3177-[1-Hydroxy-3-azabicyclo[3.1.0]hex-3-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-N-[(2S)-1,1,1-trifluoropropan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.45 (d, 1H), 8.81 (s, 1H), 8.27 (d,1H), 7.63-7.51 (m, 2H), 6.83-6.68 (m, 1H), 6.01 (d, 1H), 4.95-4.81 (m,1H), 3.92-3.84 (m, 0.5H), 3.70-3.40 (m, 2H), 3.20-3.08 (m, 1H),1.69-1.51 (m, 1H), 1.37 (d, 3H), 1.06-0.98 (m, 1H), 0.46-0.39 (m, 1H).

LC-MS (Method 3): R_(t)=1.92 min; 513 [M+H]⁺.

Example 3187-[1-Hydroxy-3-azabicyclo[3.1.0]hex-3-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-N-[(2S)-1,1,1-trifluoropropan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.45 (d, 1H), 8.81 (s, 1H), 8.27 (d,1H), 7.64-7.50 (m, 2H), 6.82-6.69 (m, 1H), 6.02 (d, 1H), 4.94-4.83 (m,1H), 3.92-3.83 (m, 0.5H), 3.69-3.40 (m, 2H), 3.20-3.09 (m, 1H),1.69-1.50 (m, 1H), 1.37 (d, 3H), 1.06-0.99 (m, 1H), 0.49-0.39 (m, 1H).

LC-MS (Method 3): R_(t)=1.92 min; 513 [M+H]⁺.

Example 319N-[(1R)-1-Cyclopropyl-2,2,2-trifluoroethyl]-1-(2,6-difluorophenyl)-7-[1-hydroxy-3-azabicyclo[3.1.0]hex-3-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP3, 150 mg (328 μmol) of the compound from Example 103Awere reacted with 53.7 mg (360 μmol) of 3-azabicyclo[3.1.0]hexan-1-olhydrochloride (racemate, 91% purity) and 200 μl (1.15 mmol) ofN,N-diisopropylethylamine in 1.5 ml of dimethylformamide. The crudeproduct was diluted with 5 ml of acetonitrile and 0.5 ml of 1N aqueoushydrochloric acid, filtered and purified by means of preparative HPLC(column: Chromatorex C18, 10 m, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient; 0 to 3 min 10% acetonitrile, to 35 min 90%acetonitrile and for a further 3 min 90% acetonitrile). 119.3 mg (69% oftheory, 98.4% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.54 (d, 1H), 8.75 (s, 1H), 8.29 (d,1H), 7.77-7.65 (m, 1H), 7.47-7.35 (m, 2H), 6.83-6.69 (m, 1H), 6.00 (d,1H), 4.43-4.31 (m, 1H), 3.92-3.82 (m, 0.5H), 3.70-3.59 (m, 0.5H),3.55-3.39 (m, 1.5H), 3.27-3.18 (m, 0.5H), 3.16-3.03 (m, 1H), 1.69-1.48(m, 1H), 1.26-1.14 (m, 1H), 1.05-0.97 (m, 1H), 0.70-0.48 (m, 3H),0.47-0.39 (m, 1H), 0.37-0.30 (m, 1H).

LC-MS (Method 3): R_(t)=2.01 min; 521 [M+H]⁺.

Example 3201-(2,4-Difluorophenyl)-4-oxo-7-(2-oxoimidazolidin-1-yl)-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 300 mg (673 μmol) of the compound from Example 67Awere reacted with 64.0 mg (707 μmol) of imidazolidinone in the presenceof 140 mg (1.01 mmol) of potassium carbonate, 27.2 mg (121 μmol) ofpalladium(II) acetate and 140 mg (242 μmol) of Xantphos in 6 ml of1,4-dioxane. Subsequently, the mixture was admixed with 10 ml of ethylacetate, washed with 1N aqueous hydrochloric acid and concentrated todryness by rotary evaporation. The residue was taken up in 10 ml of THF,250 mg of N-acetylcysteine were added and the mixture was stirred atroom temperature for 30 min. The mixture was diluted with 30 ml of ethylacetate and washed with saturated aqueous sodium hydrogencarbonatesolution, dried over sodium sulphate and filtered, and the solvent wasremoved under reduced pressure. The residue was stirred in 6 ml ofacetonitrile and 1 ml of water, the precipitate was filtered off withsuction and the mother liquor was purified by means of preparative HPLC(column: Chromatorex C18, 10 m, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient; 0 to 3 min 10% acetonitrile, to 35 min 90%acetonitrile and for a further 3 min 90% acetonitrile). 20.2 mg (5.9% oftheory, 97.1% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.31 (d, 1H), 8.78 (s, 1H), 8.56 (d,1H), 8.42 (d, 1H), 7.91-7.82 (m, 1H), 7.66-7.55 (m, 2H), 7.38-7.31 (m,1H), 4.80-4.72 (m, 1H), 3.65-3.50 (m, 2H), 3.39-3.33 (m, 2H partiallyunder the water signal), 1.95-1.82 (m, 1H), 1.72-1.59 (m, 1H), 0.98 (t,3H).

LC-MS (Method 3): R_(t)=1.89 min; 496 [M+H]⁺.

Example 3211-(2,4-Difluorophenyl)-7-(3-methyl-2-oxoimidazolidin-1-yl)-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

To a solution of 20 mg (40 μmol) of the compound from Example 320 in 1ml of 1,2-dimethoxyethane were added, while cooling with an ice bath,2.4 mg (61 μmol, 60% in mineral oil) of sodium hydride, and the mixturewas stirred for a further 30 min. The mixture was warmed to roomtemperature, 5.0 μl (81 μmol) of iodomethane were added and the mixturewas stirred at 80° C. overnight. Subsequently, the volume of the mixturewas concentrated under reduced pressure, and the residue was taken up in3 ml of acetonitrile, 0.5 ml of water and 1 ml of DMSO, and purified bymeans of preparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm,solvent: acetonitrile/0.05% formic acid gradient; 0 to 3 min 10%acetonitrile, to 35 min 90% acetonitrile and for a further 3 min 90%acetonitrile). 5.4 mg (26% of theory, 99% purity) of the title compoundwere obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.31 (d, 1H), 8.78 (s, 1H), 8.57 (d,1H), 8.43 (d, 1H), 7.91-7.81 (m, 1H), 7.63-7.56 (m, 1H), 7.38-7.31 (m,1H), 4.81-4.71 (m, 1H), 3.57-3.36 (m, 4H), 2.79 (s, 3H), 1.94-1.84 (m,1H), 1.72-1.59 (m, 1H), 0.98 (t, 3H).

LC-MS (Method 1): R_(t)=1.16 min; 510 [M+H]⁺.

Example 3221-(2-Chloro-4,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-N-[(2S)-1-(trifluoromethoxy)propan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP3, 51.7 mg (104 μmol) of the compound from Example 112Awere reacted with 16.0 mg (115 μmol) of (3R,4R)-pyrrolidine-3,4-diolhydrochloride and 63.5 μl (365 μmol) of N,N-diisopropylethylamine in 1ml of dimethylformamide. The crude product was acidified with 2 ml ofacetonitrile and 1N aqueous hydrochloric acid and purified by means ofpreparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm, solvent:acetonitrile/0.05% formic acid gradient; 0 to 3 min 10% acetonitrile, to35 min 90% acetonitrile and for a further 3 min 90% acetonitrile). 48 mg(82% of theory, 100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.14-10.09 (m, 1H), 8.66 (s, 1H),8.27 (d, 1H), 7.75-7.65 (m, 2H), 6.75 (d, 1H), 5.24-5.20 (m, 1H),5.15-5.11 (m, 1H), 4.38-4.29 (m, 1H), 4.21-4.13 (m, 2H), 4.06-4.02 (m,1H), 3.93-3.88 (m, 1H), 3.64-3.57 (m, 1H), 3.24-3.16 (m, 1H), 3.06-2.98(m, 1H), 1.28-1.21 (m, 3H).

LC-MS (Method 3): R_(t)=1.68 min; m/z=563 [M+H]⁺.

Example 323 N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-4-oxo-7-(2-oxoimidazolidin-1-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 15.0 g (37.1 mmol) of the compound from Example 113Awere reacted with 7.82 g (44.5 mmol) of(1S)₁-cyclopropyl-2,2,2-trifluoroethanamine hydrochloride in thepresence of 16.9 g (44.5 mmol) of HATU and 16.2 ml (92.8 mmol) ofN,N-diisopropylethylamine in 400 ml of dimethylformamide. On completionof conversion, the reaction solution was stirred into water and adjustedto pH 3. The mixture was extracted with ethyl acetate and the phaseswere separated. The organic phase was washed with water, dried oversodium sulphate, filtered and concentrated. The residue was stirred inacetonitrile, filtered off with suction after 1 h, washed and driedunder high vacuum. 9.3 g (48% of theory, 99% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.36 (d, 1H), 8.99 (s, 1H), 8.57 (d,1H), 8.44 (d, 1H), 7.67 (s, 1H), 7.62-7.53 (m, 2H), 4.47-4.34 (m, 1H),3.64-3.56 (m, 2H), 3.39-3.32 (m, 2H), 1.28-1.17 (m, 1H), 0.71-0.50 (m,3H), 0.39-0.31 (m, 1H).

LC-MS (Method 3): R_(t)=1.94 min; m/z=526 [M+H]⁺.

Example 3247-[3-Hydroxy-3-methylpyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP3, 100 mg (216 μmol) of the compound from Example 100Cand 39.6 mg (90% purity, 259 μmol) of 3-methylpyrrolidin-3-olhydrochloride were reacted in the presence of 130 μl (750 μmol) ofN,N-diisopropylethylamine in 1.0 ml of DMF. The reaction mixture wasdiluted with 0.5 ml of acetonitrile and was purified by means ofpreparative HPLC (column: Chromatorex C18, 10 m, 125×30 mm, solvent:acetonitrile/0.05% formic acid gradient; 0 to 3 min 10% acetonitrile, to35 min 90% acetonitrile and for a further 3 min 90% acetonitrile). 93.5mg (81% of theory, 99% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: −0.008 (2.44), 0.008 (1.51), 0.952(7.58), 0.970 (16.00), 0.988 (7.79), 1.249 (9.47), 1.323 (10.19), 1.602(1.14), 1.621 (1.57), 1.627 (1.40), 1.637 (1.85), 1.646 (1.66), 1.655(1.60), 1.663 (1.71), 1.681 (1.29), 1.795 (2.67), 1.814 (1.90), 1.832(0.86), 1.850 (1.62), 1.859 (1.90), 1.868 (1.90), 1.878 (2.33), 1.885(2.43), 1.895 (2.50), 1.904 (2.87), 1.913 (3.39), 1.929 (1.83), 2.941(1.33), 2.971 (1.75), 3.119 (1.67), 3.150 (1.26), 3.223 (2.27), 3.239(1.69), 3.288 (2.21), 3.341 (2.64), 3.364 (2.32), 3.391 (0.81), 3.548(2.35), 3.566 (1.53), 4.732 (1.56), 4.752 (1.44), 4.820 (3.48), 4.893(3.76), 6.703 (2.03), 6.725 (2.13), 6.762 (1.95), 6.785 (1.84), 7.533(1.97), 7.554 (3.99), 7.574 (3.36), 8.247 (2.36), 8.270 (4.17), 8.293(1.97), 8.792 (5.29), 8.799 (5.47), 10.424 (5.03), 10.448 (4.79).

LC-MS Method 3): R_(t)=2.06 min; MS (ESIpos): m/z=529 [M+H]⁺

Example 3257-[(4S)-4-Hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 100 mg (216 μmol) of the compound from Example 100Cwere reacted with 26.2 mg (259 μmol) of (4S)-4-hydroxypyrrolidin-2-onein the presence of 44.7 mg (323 μmol) of potassium carbonate, 8.71 mg(38.8 μmol) of palladium(II) acetate and 44.9 mg (77.6 μmol) of Xantphosin 2.0 ml of 1,4-dioxane. Subsequently, the reaction mixture wasconcentrated. It was acidified with 1N aqueous hydrochloric acid,admixed with 3 ml of acetonitrile and filtered. The filtrate waspurified by means of preparative HPLC (column: Chromatorex C18, 10 m,125×30 mm, solvent: acetonitrile/0.05% formic acid gradient; 0 to 3 min.10% acetonitrile to 35 min. 90% acetonitrile and a further 3 min. 90%acetonitrile), and 87.9 mg (76% of theory, 99% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: −0.008 (3.32), 0.008 (3.18), 0.965(7.20), 0.984 (16.00), 1.002 (7.81), 1.632 (1.07), 1.649 (1.52), 1.666(1.70), 1.675 (1.50), 1.692 (1.78), 1.710 (1.36), 1.866 (1.31), 1.877(1.46), 1.884 (1.48), 1.895 (1.68), 2.355 (3.56), 2.399 (4.11), 2.711(0.71), 2.916 (3.44), 2.931 (3.68), 2.959 (3.12), 2.974 (3.03), 3.287(4.13), 3.463 (3.72), 3.493 (4.43), 3.673 (3.24), 3.686 (3.90), 3.703(2.95), 3.715 (2.59), 4.290 (2.79), 4.763 (1.42), 5.331 (7.89), 5.340(7.81), 7.595 (2.27), 7.602 (2.65), 7.617 (4.31), 7.625 (4.51), 7.639(2.65), 7.645 (2.27), 8.532 (10.26), 8.554 (12.42), 8.707 (12.88), 8.729(9.97), 9.072 (15.90), 10.103 (5.12), 10.127 (4.94).

LC-MS (Method 3): Rt=1.90 min; MS (ESIpos): m/z=529 [M+H]⁺

Example 326N-[1-Cyclopropyl-2,2,2-trifluoroethyl]-1-(2,6-difluorophenyl)-7-[3-hydroxy-3-methylpyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Racemic Diastereomer Mixture)

According to GP3, 150 mg (328 μmol) of the compound from Example 102Aand 60.1 mg (90% purity, 393 μmol) of 3-methylpyrrolidin-3-olhydrochloride were reacted in the presence of 200 μl (1.15 mmol) ofN,N-diisopropylethylamine in 1.5 ml of DMF. The reaction mixture wasdiluted with 0.5 ml of acetonitrile and was purified by means ofpreparative HPLC (column: Chromatorex C18, 10 m, 125×30 mm, solvent:acetonitrile/0.05% formic acid gradient; 0 to 3 min 10% acetonitrile, to35 min 90% acetonitrile and for a further 3 min 90% acetonitrile). 147mg (85% of theory, 99% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: −0.008 (2.22), 0.008 (2.01), 0.325(2.15), 0.336 (3.45), 0.349 (3.49), 0.361 (2.61), 0.373 (1.29), 0.509(2.38), 0.520 (3.47), 0.532 (3.03), 0.547 (2.85), 0.556 (2.52), 0.568(3.35), 0.578 (2.96), 0.589 (2.71), 0.599 (2.27), 0.612 (1.41), 0.626(1.71), 0.637 (1.90), 0.648 (3.05), 0.658 (2.82), 0.663 (2.80), 0.671(2.75), 0.683 (1.22), 0.693 (0.88), 1.166 (0.72), 1.179 (1.48), 1.187(2.19), 1.199 (3.96), 1.220 (16.00), 1.240 (2.11), 1.314 (13.09), 1.769(3.67), 1.786 (2.27), 1.900 (3.26), 1.917 (2.19), 2.891 (1.81), 2.922(2.43), 3.079 (2.24), 3.107 (1.74), 3.169 (3.01), 3.186 (2.19), 3.289(3.10), 3.335 (3.65), 3.357 (3.14), 3.385 (1.15), 3.542 (3.08), 4.353(1.85), 4.374 (3.17), 4.396 (3.12), 4.416 (1.64), 4.806 (4.85), 4.886(4.93), 6.703 (2.56), 6.724 (2.64), 6.760 (2.57), 6.783 (2.48), 7.386(4.04), 7.408 (8.42), 7.431 (4.69), 7.694 (2.63), 7.714 (2.48), 7.729(1.34), 8.258 (2.85), 8.280 (5.59), 8.303 (2.71), 8.724 (5.94), 8.736(6.08), 10.574 (7.24), 10.598 (6.96).

LC-MS (Method 1): Rt=1.14 min; MS (ESIpos): m/z=523 [M+H]⁺

Example 3271-(2,6-Difluorophenyl)-7-[3-hydroxy-3-methylpyrrolidin-1-yl]-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP3, 150 mg (336 μmol) of the compound from Example 114Aand 61.7 mg (90% purity, 404 μmol) of 3-methylpyrrolidin-3-olhydrochloride were reacted in the presence of 205 μl (1.18 mmol) ofN,N-diisopropylethylamine in 1.6 ml of DMF. The reaction mixture wasdiluted with 0.5 ml of acetonitrile and was purified by means ofpreparative HPLC (column: Chromatorex C18, 10 m, 125×30 mm, solvent:acetonitrile/0.05% formic acid gradient; 0 to 3 min 10% acetonitrile, to35 min 90% acetonitrile and for a further 3 min 90% acetonitrile). 148mg (85% of theory, 99% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: −0.008 (1.74), 0.008 (1.59), 0.953(7.22), 0.972 (16.00), 0.990 (7.86), 1.221 (9.41), 1.314 (9.55), 1.604(1.11), 1.622 (1.51), 1.629 (1.32), 1.639 (1.80), 1.647 (1.62), 1.657(1.53), 1.664 (1.74), 1.683 (1.31), 1.752 (1.35), 1.769 (2.70), 1.786(1.71), 1.842 (0.74), 1.851 (1.53), 1.861 (1.80), 1.870 (2.02), 1.879(2.75), 1.886 (2.65), 1.897 (3.47), 1.904 (3.28), 1.915 (2.43), 2.074(2.15), 2.892 (1.28), 2.922 (1.76), 3.078 (1.63), 3.108 (1.27), 3.171(2.19), 3.187 (1.57), 3.289 (2.34), 3.335 (2.76), 3.357 (2.27), 3.384(0.79), 3.541 (2.31), 3.559 (1.53), 4.706 (0.81), 4.730 (1.48), 4.750(1.39), 4.765 (0.81), 4.806 (3.46), 4.885 (3.51), 6.701 (1.85), 6.723(1.98), 6.759 (1.91), 6.782 (1.87), 7.389 (2.83), 7.411 (5.95), 7.433(3.33), 7.680 (1.06), 7.697 (1.88), 7.714 (1.77), 7.734 (0.89), 8.254(1.99), 8.276 (3.83), 8.299 (1.88), 8.733 (3.67), 8.745 (3.76), 10.440(4.71), 10.464 (4.56).

LC-MS (Method 1): R_(t)=1.12 min; MS (ESIpos): m/z=511 [M+H]⁺

Example 3281-(2,4-Difluorophenyl)-7-(3-methoxy-3-methyazetidin-1-yl)-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP3, 80.0 mg (179 μmol) of the compound from Example 67Aand 29.6 mg (215 μmol) of 3-methoxy-3-methylazetidine hydrochloride werereacted in the presence of 110 μl (628 μmol) ofN,N-diisopropylethylamine in 0.83 ml of DMF. The reaction mixture wasdiluted with 0.5 ml of acetonitrile and was purified by means ofpreparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm, solvent:acetonitrile/0.05% formic acid gradient; 0 to 3 min 10% acetonitrile, to35 min 90% acetonitrile and for a further 3 min 90% acetonitrile). 74.2mg (80% of theory, 99% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.945 (1.92), 0.964 (4.32), 0.982(2.11), 1.408 (8.86), 3.155 (16.00), 6.612 (2.62), 6.634 (2.63), 8.293(2.95), 8.315 (2.81), 8.610 (3.06), 10.461 (1.38), 10.484 (1.33).

LC-MS (Method 3): R_(t)=2.29 min; MS (ESIpos): m/z=511 [M+H]⁺

Example 3291-(2,6-Difluorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2S)-1,1,1-trifluoropropan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 100 mg (232 μmol) of the compound from Example 106Awere reacted with 25.8 mg (255 μmol) of (4S)-4-hydroxypyrrolidin-2-onein the presence of 48.0 mg (347 μmol) of potassium carbonate, 5.2 mg (23μmol) of palladium(II) acetate and 26.6 mg (46.3 μmol) of Xantphos in3.0 ml of 1,4-dioxane. Subsequently, the reaction mixture wasconcentrated. The residue was dissolved with 0.5 ml of water and with 3ml of acetonitrile and purified by means of preparative HPLC (column:Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05% formicacid gradient; 0 to 3 min. 10% acetonitrile to 35 min. 90% acetonitrileand a further 3 min. 90% acetonitrile), and 77.9 mg (68% of theory, 100%purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: −0.008 (4.64), 0.008 (4.39), 0.146(0.56), 1.388 (15.95), 1.405 (16.00), 2.074 (1.46), 2.346 (3.39), 2.367(0.65), 2.389 (3.97), 2.711 (0.60), 2.901 (3.40), 2.916 (3.51), 2.944(3.10), 2.959 (3.05), 3.288 (3.83), 3.415 (3.37), 3.445 (4.29), 3.615(3.18), 3.627 (3.85), 3.644 (2.88), 3.656 (2.54), 4.241 (1.11), 4.254(2.54), 4.262 (2.49), 4.277 (1.01), 4.890 (1.13), 4.913 (1.59), 4.931(1.71), 4.950 (1.13), 5.322 (7.78), 5.332 (7.60), 7.433 (2.03), 7.445(2.54), 7.456 (4.16), 7.467 (4.37), 7.478 (2.84), 7.490 (2.29), 7.724(0.88), 7.740 (1.87), 7.746 (1.94), 7.756 (1.31), 7.762 (3.37), 7.768(1.31), 7.778 (1.82), 7.783 (1.82), 7.800 (0.83), 8.527 (10.07), 8.549(12.17), 8.704 (12.31), 8.726 (9.65), 9.018 (12.68), 10.169 (4.80),10.192 (4.62).

LC-MS (Method 3): R_(t)=1.73 min; MS (ESIpos): m/z=497 [M+H]⁺

Example 3307-[(4S)-4-Hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-N-[(2S)-1,1,1-trifluoropropan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 300 mg (667 μmol) of the compound from Example 107Awere reacted with 74.2 mg (734 μmol) of (4S)-4-hydroxypyrrolidin-2-onein the presence of 138 mg (1.00 mmol) of potassium carbonate, 15 mg (67μmol) of palladium(II) acetate and 27 mg (46 μmol) of Xantphos in 8.6 mlof 1,4-dioxane. Subsequently, the reaction mixture was concentrated.Subsequently, the mixture was acidified with 5 ml of 1N aqueoushydrochloric acid and the pH was monitored. 140 mg of N-acetylcysteinewere added and the mixture was stirred at RT for a further 15 min. Themixture was introduced into a separating funnel and diluted with 15 mlof saturated aqueous sodium hydrogencarbonate solution and 20 ml ofethyl acetate. The phases were separated and the aqueous phase wasextracted three times with ethyl acetate. The combined organic phaseswere dried over magnesium sulphate and filtered, and the solvent wasremoved under reduced pressure. The residue was dissolved in 9 ml ofacetonitrile and 3 ml of DMSO and purified in four runs by means ofpreparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm, solvent:acetonitrile/0.05% formic acid gradient; 0 to 3 min. 15% acetonitrile to35 min. 85% acetonitrile and a further 3 min. 85% acetonitrile), and208.4 mg (60% of theory, 99% purity) of the title compound wereobtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.17 (d, 1H), 9.07 (s, 1H), 8.71 (d,1H), 8.54 (d, 1H), 7.66-7.57 (m, 2H), 5.34 (d, 1H), 4.99-4.86 (m, 1H),4.32-4.26 (m, 1H), 3.69 (dd, 1H), 3.48 (d, 1H), 2.94 (dd, 1H), 2.38 (d,1H), 1.39 (d, 3H).

LC-MS (Method 3): R_(t)=1.74 min; MS (ESIpos): m/z=515 [M+H]⁺

Example 3317-[(2R,4S)-4-Hydroxy-2,4-dimethylpyrrolidin-1-yl]-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP3, 30.8 mg (66.4 μmol) of the compound from Example 115Aand 24.0 mg (95% purity, 99.6 μmol) of the compound from Example 116Awere reacted in the presence of 40.0 μl (232 μmol) ofN,N-di-iso-propylethylamine in 640 μl of DMF. The reaction mixture wasdiluted with 0.5 ml of acetonitrile and was purified by means ofpreparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm, solvent:acetonitrile/0.05% formic acid gradient; 0 to 3 min 15% acetonitrile, to35 min 85% acetonitrile and for a further 3 min 85% acetonitrile). 30.1mg (83% of theory, 99% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: −0.150 (0.64), −0.008 (5.62), 0.008(5.53), 0.146 (0.72), 0.951 (7.19), 0.970 (16.00), 0.988 (8.00), 1.046(4.51), 1.147 (0.98), 1.271 (7.87), 1.603 (1.19), 1.620 (2.00), 1.628(2.26), 1.637 (2.64), 1.646 (2.21), 1.655 (2.51), 1.663 (3.02), 1.681(1.74), 1.850 (1.28), 1.860 (1.57), 1.869 (1.53), 1.879 (1.87), 1.884(1.57), 1.895 (1.40), 1.904 (1.23), 1.913 (0.98), 2.019 (1.02), 2.328(0.60), 2.367 (1.02), 2.670 (0.72), 2.710 (1.15), 3.288 (6.51), 3.337(2.51), 3.483 (1.49), 3.794 (1.11), 4.722 (1.36), 4.877 (2.94), 6.711(1.53), 7.546 (3.40), 7.569 (6.00), 7.589 (3.23), 8.251 (4.38), 8.273(4.30), 8.817 (5.11), 10.416 (5.45), 10.440 (5.32).

LC-MS (Method 3): Rt=2.13 min; MS (ESIpos): m/z=543 [M+H]⁺

Example 3327-[(4S)-4-Hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 20.0 g (47.7 mmol) of the compound from Example 117Awere reacted with 9.36 g (57.2 mmol) of(2S)-1,1,1-trifluorobutan-2-amine hydrochloride in the presence of 27.2g (71.5 mmol) of HATU and 20.8 ml (119 mmol) ofN,N-diisopropylethylamine in 250 ml of dimethylformamide. The reactionmixture was extracted by stirring in ice-water and a little aqueoushydrochloric acid, and the precipitate was filtered off with suction andwashed with water. The crude product was combined with a second batchwhich proceeded from 2.00 g of the compound from Example 117A in ananalogous mode of operation. The combined residue was purified twice bymeans of normal phase chromatography (dichloromethane-methanol 95:5 v/vand petroleum ether-ethyl acetate 1:1, v/v towarddichloromethane-methanol 9:1, v/v). Finally, the product was stirredwith tert-butyl methyl ether and the precipitate was filtered off withsuction and washed with tert-butyl methyl ether. 20.3 g (81% of theory,100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.11 (d, 1H), 8.72 (d, 1H), 8.54 (d,1H), 7.66-7.58 (m, 2H), 5.35-5.31 (m, 1H), 4.83-4.70 (m, 1H), 4.33-4.26(m, 1H), 3.69 (dd, 1H), 3.47 (d, 1H), 2.95 (dd, 1H), 2.38 (d, 1H),1.95-1.84 (m, 1H), 1.74-1.60 (m, 1H), 0.98 (t, 3H).

LC-MS (Method 3): R_(t)=1.86 min; 529 [M+H]⁺.

Example 3331-(2,6-Difluorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 150 mg (336 μmol) of the compound from Example 114Awere reacted with 34.0 mg (336 μmol) of (4S)-4-hydroxypyrrolidin-2-onein the presence of 69.8 mg (505 μmol) of potassium carbonate, 13.6 mg(60.6 μmol) of palladium(II) acetate and 70.1 mg (121 μmol) of Xantphosin 3.1 ml of 1,4-dioxane. Subsequently, the reaction mixture wasconcentrated. The residue was diluted in 0.5 ml of acetonitrile and waspurified by means of preparative HPLC (column: Chromatorex C18, 10 m,125×30 mm, solvent: acetonitrile/0.05% formic acid gradient; 0 to 3 min15% acetonitrile, to 35 min 85% acetonitrile and for a further 3 min 85%acetonitrile). 91.7 mg (52% of theory, 98% purity) of the title compoundwere obtained.

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.150 (0.56), −0.008 (4.35), 0.008(4.37), 0.965 (7.27), 0.983 (16.00), 1.002 (7.82), 1.147 (0.70), 1.633(1.04), 1.651 (1.43), 1.658 (1.32), 1.668 (1.70), 1.677 (1.64), 1.694(1.72), 1.712 (1.37), 1.868 (1.33), 1.877 (1.66), 1.886 (1.59), 1.896(1.80), 1.902 (1.61), 1.921 (1.18), 1.931 (1.03), 2.074 (2.86), 2.347(3.58), 2.390 (4.26), 2.712 (0.60), 2.905 (3.75), 2.920 (3.83), 2.948(3.25), 2.963 (3.15), 3.288 (4.57), 3.414 (3.64), 3.444 (4.51), 3.619(3.35), 3.631 (3.95), 3.649 (3.06), 3.661 (2.75), 4.255 (2.75), 4.783(1.37), 5.322 (7.99), 5.331 (7.85), 7.434 (2.17), 7.447 (2.84), 7.455(4.53), 7.469 (4.89), 7.479 (3.23), 7.492 (2.57), 7.725 (0.91), 7.741(2.07), 7.747 (2.07), 7.763 (3.68), 7.779 (1.86), 7.784 (1.95), 7.800(0.99), 8.530 (10.39), 8.553 (12.44), 8.712 (12.73), 8.734 (9.89), 9.023(14.97), 10.118 (4.99), 10.142 (4.86).

LC-MS (Method 3): R_(t)=1.85 min; MS (ESIpos): m/z=511 [M+H]⁺

Example 3341-(2-Chloro-4,6-difluorophenyl)-7-[(2R,4S)-4-hydroxy-2,4-dimethylpyrrolidin-1-yl]-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP3, 19.0 mg (39.7 μmol) of the compound from Example 108Cand 10.5 mg (95% purity, 43.6 μmol) of the compound from Example 116Awere reacted in the presence of 24.0 μl (140 μmol) ofN,N-diisopropylethylamine in 1.5 ml of DMF. The reaction mixture wasdiluted with 4 ml of acetonitrile and 0.5 ml of water and purified bymeans of preparative HPLC (column: Kromasil C18, 10 μm, 250×20 mm,solvent: acetonitrile/0.05% formic acid gradient; 0 to 3 min 10%acetonitrile, to 35 min 90% acetonitrile and for a further 3 min 90%acetonitrile). 15.1 mg (67% of theory, 99% purity) of the title compoundwere obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: −0.149 (0.94), −0.008 (16.00), 0.008(6.41), 0.146 (0.76), 0.949 (3.46), 0.968 (7.24), 0.978 (8.76), 0.996(5.30), 1.266 (6.27), 1.648 (2.13), 1.886 (1.12), 2.000 (0.86), 2.710(0.76), 3.288 (13.91), 3.334 (2.74), 3.740 (1.05), 4.733 (1.23), 4.869(2.34), 6.682 (1.26), 7.712 (2.74), 7.734 (2.92), 8.253 (2.81), 8.275(2.63), 8.768 (2.70), 10.438 (3.53), 10.462 (3.28).

LC-MS (Method 3): R_(t)=2.16 min; MS (ESIpos): m/z=559 [M+H]⁺

Example 3351-(2-Chloro-4,6-difluorophenyl)-7-(3,3-dimethyl-2-oxopyrrolidin-1-yl)-4-oxo-N-[(2S)-1,1,1-trifluoropropan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 50.0 mg (107 μmol) of the compound from Example 111Awere reacted with 12.1 mg (107 μmol) of 3,3-dimethylpyrrolidin-2-one inthe presence of 22.2 mg (161 μmol) of potassium carbonate, 4.3 mg (19μmol) of palladium(II) acetate and 22.3 mg (38.6 μmol) of Xantphos in980 μl of 1,4-dioxane. Subsequently, the reaction mixture was acidifiedwith 0.5 ml of 1N aqueous hydrochloric acid and concentrated. Theresidue was purified by means of normal phase chromatography(cyclohexane-ethyl acetate gradient). 34.0 mg (58% of theory, 99%purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.008 (1.16), 0.008 (0.85), 1.136(16.00), 1.385 (2.51), 1.391 (2.58), 1.403 (2.55), 1.409 (2.44), 1.861(1.36), 1.879 (2.82), 1.896 (1.41), 3.288 (1.97), 3.469 (0.75), 3.487(1.42), 3.499 (1.18), 7.738 (0.64), 7.745 (0.94), 7.760 (0.98), 7.769(0.99), 7.781 (0.72), 8.548 (2.50), 8.570 (3.07), 8.704 (3.06), 8.726(2.32), 9.033 (2.57), 9.037 (2.49), 10.166 (1.26), 10.189 (1.19).

LC-MS (Method 1): R_(t)=1.26 min; MS (ESIpos): m/z=543 [M+H]⁺

Example 3361-(2-Chloro-4,6-difluorophenyl)-7-(3,3-dimethyl-2-oxopyrrolidin-1-yl)-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 50.0 mg (104 μmol) of the compound from Example 108Cwere reacted with 11.8 mg (104 μmol) of 3,3-dimethylpyrrolidin-2-one inthe presence of 21.6 mg (156 μmol) of potassium carbonate, 4.2 mg (19μmol) of palladium(II) acetate and 21.7 mg (37.5 μmol) of Xantphos in950 μl of 1,4-dioxane. Subsequently, the reaction mixture was acidifiedwith 0.5 ml of aqueous 1N hydrochloric acid and concentrated. Theresidue was dissolved in 8 ml of dichloromethane and purified by meansof normal phase chromatography (cyclohexane-ethyl acetate gradient).33.7 mg (58% of theory, 99% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.008 (0.66), 0.008 (0.63), 0.961(0.88), 0.971 (1.05), 0.980 (2.05), 0.990 (2.04), 0.998 (1.10), 1.008(0.96), 1.138 (16.00), 1.863 (1.33), 1.880 (2.84), 1.898 (1.63), 3.288(1.03), 3.482 (0.71), 3.490 (1.11), 3.500 (1.33), 3.518 (0.64), 7.747(0.84), 7.763 (0.85), 7.770 (0.93), 8.551 (2.23), 8.574 (2.77), 8.711(2.67), 8.734 (2.08), 9.040 (3.76), 10.112 (0.77), 10.116 (0.79), 10.136(0.76), 10.140 (0.74).

LC-MS (Method 1): R_(t)=1.31 min; MS (ESIpos): m/z=557 [M+H]⁺

Example 3371-(2,4-Difluorophenyl)-4-oxo-7-(2-oxopyrrolidin-1-yl)-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 100 mg (224 μmol) of the compound from Example 67Awere reacted with 21.0 mg (224 μmol) of pyrrolidin-2-one in the presenceof 46.5 mg (336 μmol) of potassium carbonate, 2.5 mg (11 μmol) ofpalladium(II) acetate and 13.0 mg (22.4 μmol) of Xantphos in 2.0 μl of1,4-dioxane. Subsequently, the reaction mixture was acidified with 0.5ml of aqueous 1N hydrochloric acid and concentrated. The residue wasdissolved in 8 ml of dichloromethane and purified by means of normalphase chromatography (cyclohexane-ethyl acetate gradient). Finally, theresidue was stirred with 4 ml of acetonitrile, 3 ml of water and 2 ml ofDMSO, and the precipitate was filtered off with suction, washed withwater and dried under high vacuum. 60.4 mg (52% of theory, 95% purity)of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.149 (0.63), −0.008 (4.86), 0.008(4.78), 0.146 (0.63), 0.959 (7.14), 0.978 (16.00), 0.996 (7.84), 1.148(0.86), 1.175 (0.71), 1.233 (0.86), 1.398 (1.41), 1.625 (1.10), 1.643(1.41), 1.651 (1.25), 1.660 (1.73), 1.669 (1.57), 1.678 (1.49), 1.686(1.73), 1.704 (1.33), 1.867 (1.33), 1.876 (1.49), 1.885 (1.57), 1.895(1.73), 1.901 (1.49), 1.911 (1.41), 1.920 (1.49), 1.930 (1.80), 1.948(3.06), 1.962 (4.24), 1.988 (3.53), 2.001 (1.18), 2.328 (0.71), 2.366(1.18), 2.564 (3.69), 2.569 (3.76), 2.582 (5.65), 2.591 (6.12), 2.603(3.14), 2.610 (2.82), 2.670 (0.71), 2.710 (1.25), 3.289 (7.69), 3.533(2.04), 3.551 (3.76), 3.574 (3.84), 3.591 (2.04), 4.765 (1.41), 7.343(1.33), 7.362 (2.75), 7.383 (1.49), 7.591 (1.80), 7.598 (1.88), 7.614(2.43), 7.617 (2.59), 7.621 (2.67), 7.624 (2.35), 7.640 (1.88), 7.647(1.80), 7.860 (1.88), 7.880 (1.80), 8.500 (9.25), 8.522 (11.22), 8.690(11.37), 8.713 (9.18), 8.850 (5.65), 10.209 (4.78), 10.233 (4.63).

LC-MS (Method 1): R_(t)=1.13 min; MS (ESIpos): m/z=495 [M+H]⁺

Example 338 1-(2-Chloro-4,6-difluorophenyl)-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 100 mg (203 μmol) of the compound from Example 110Awere reacted with 22.6 mg (223 μmol) of pyrrolidin-2-one in the presenceof 42.1 mg (305 μmol) of potassium carbonate, 2.3 mg (10 μmol) ofpalladium(II) acetate and 11.8 mg (20.3 μmol) of Xantphos in 1.8 μl of1,4-dioxane. On completion of conversion, N-acetylcysteine was added andthe mixture was stirred at room temperature for a further 0.5 h. Themixture was diluted with 20 ml of ethyl acetate and extracted withsaturated aqueous sodium hydrogencarbonate solution. The organic phasewas concentrated and stirred in 4 ml of acetonitrile and 3 ml of water.The precipitate was filtered off with suction and dried under highvacuum. The mother liquor was purified by means of preparative HPLC(column: Kromasil C18, 10 μm, 250×20 mm, solvent: acetonitrile/0.05%formic acid gradient; 0 to 3 min 10% acetonitrile, to 35 min 90%acetonitrile and for a further 3 min 90% acetonitrile) and the productfractions were combined with the precipitate. Finally, by normal phasechromatography (cyclohexane-ethyl acetate gradient), 43.2 mg (36% oftheory; 95% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]=10.27 (d, 1H), 9.03 (s, 1H), 8.73 (d,1H), 8.54 (d, 1H), 7.82-7.72 (m, 2H), 5.33 (d, 1H), 4.46-4.34 (m, 1H),4.31-4.25 (m, 1H), 3.69-3.60 (m, 1H), 3.46-3.38 (m, 1H), 2.94 (dd, 1H),2.37 (d, 1H), 1.28-1.19 (m, 1H), 0.71-0.51 (m, 3H), 0.39-0.30 (m, 1H).

LC-MS (Method 3): R_(t)=1.94 min; MS (ESIpos): m/z=557 [M+H]⁺

Example 3397-[(4S)-4-Hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2S)-1-(trifluoromethoxy)propan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 80 mg (167 μmol) of the compound from Example 118Awere reacted with 18.5 mg (183 μmol) of (4S)-4-hydroxypyrrolidin-2-onein the presence of 34.6 mg (250 μmol) of potassium carbonate, 1.9 mg(8.3 μmol) of palladium(II) acetate and 9.65 mg (16.7 μmol) of Xantphosin 1.7 ml of 1,4-dioxane. 80 mg of N-acetylcysteine were added and themixture was stirred at RT for 30 min. The reaction mixture was admixedwith 30 ml of ethyl acetate, washed with saturated aqueous sodiumhydrogencarbonate solution, dried over sodium sulphate, filtered andconcentrated. The residue was purified by means of preparative HPLC(column: Chromatorex C18, 10 m, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient; 0 to 3 min 10% acetonitrile, to 35 min 90%acetonitrile and for a further 3 min 90% acetonitrile). 12.5 mg (14% oftheory, 100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: −0.149 (0.63), −0.008 (5.28), 0.008(5.09), 0.146 (0.59), 1.258 (15.87), 1.275 (16.00), 2.053 (0.86), 2.353(2.84), 2.396 (3.32), 2.912 (2.80), 2.926 (2.94), 2.955 (2.59), 2.970(2.52), 3.291 (2.86), 3.462 (2.92), 3.492 (3.55), 3.670 (2.57), 3.682(3.15), 3.700 (2.40), 3.712 (2.10), 4.158 (0.69), 4.169 (1.05), 4.183(4.77), 4.189 (5.49), 4.194 (5.66), 4.201 (5.45), 4.214 (0.90), 4.226(0.95), 4.296 (2.19), 4.351 (1.26), 4.369 (1.77), 4.386 (1.24), 5.329(4.44), 5.338 (4.42), 7.588 (1.96), 7.595 (2.23), 7.608 (3.28), 7.618(3.36), 7.625 (1.89), 7.631 (2.21), 7.638 (1.77), 8.511 (7.76), 8.533(9.40), 8.693 (9.48), 8.716 (7.55), 8.990 (11.46), 9.825 (4.04), 9.845(3.93).

LC-MS (Method 1): R_(t)=0.97 min; MS (ESIpos): m/z=545 [M+H]⁺

Example 3401-(2-Chloro-4,6-difluorophenyl)-4-oxo-7-(2-oxoimidazolidin-1-yl)-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 100 mg (208 μmol) of the compound from Example 108Cwere reacted with 89.6 mg (1.04 mmol) of imidazolidin-2-one in thepresence of 43.2 mg (312 μmol) of potassium carbonate, 2.3 mg (10 μmol)of palladium(II) acetate and 12.0 mg (20.8 μmol) of Xantphos in 6.0 mlof 1,4-dioxane. Subsequently, the reaction mixture was acidified with0.5 ml of 1N aqueous hydrochloric acid and concentrated. The residue wasdissolved in 8 ml of dichloromethane and purified by means of normalphase chromatography (cyclohexane-ethyl acetate gradient). 50.0 mg (43%of theory, 95% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: −0.149 (0.90), −0.008 (7.68), 0.008(7.59), 0.146 (0.93), 0.958 (3.13), 0.968 (3.74), 0.977 (7.30), 0.986(7.36), 0.995 (3.94), 1.005 (3.45), 1.234 (0.99), 1.398 (0.81), 1.657(1.22), 1.668 (1.10), 1.676 (1.22), 1.685 (0.93), 1.693 (0.96), 1.872(1.01), 1.891 (1.16), 2.074 (1.80), 2.367 (0.67), 2.711 (0.70), 3.288(4.46), 3.340 (6.90), 3.360 (4.38), 3.514 (0.93), 3.523 (2.41), 3.534(2.67), 3.542 (4.14), 3.553 (3.10), 3.574 (1.74), 4.757 (1.10), 7.663(6.00), 7.691 (1.28), 7.698 (1.80), 7.713 (1.97), 7.721 (3.16), 7.738(3.16), 7.744 (3.77), 7.759 (2.26), 8.427 (8.20), 8.449 (10.75), 8.554(10.61), 8.577 (7.65), 8.959 (16.00), 10.215 (2.72), 10.219 (2.78),10.239 (2.72), 10.244 (2.64).

LC-MS (Method 3): R_(t)=1.98 min; MS (ESIpos): m/z=530 [M+H]⁺

Example 3414-Oxo-7-(2-oxoimidazolidin-1-yl)-1-(2,4,6-trifluorophenyl)-N-[(2S)-1,1,1-trifluoropropan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 51.0 mg (113 μmol) of the compound from Example 107Awere reacted with 97.6 mg (1.13 mmol) of imidazolidin-2-one in thepresence of 23.5 mg (170 μmol) of potassium carbonate, 2.6 mg (11 μmol)of palladium(II) acetate and 13.1 mg (22.7 μmol) of Xantphos in 1.1 mlof 1,4-dioxane. 50 mg of N-acetylcysteine were added and the mixture wasstirred at RT for 30 min. The reaction mixture was admixed with 30 ml ofethyl acetate, washed with saturated aqueous sodium hydrogencarbonatesolution, dried over sodium sulphate, filtered and concentrated. Theresidue was purified by means of preparative HPLC (column: ChromatorexC18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05% formic acid gradient;0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrile and for afurther 3 min 90% acetonitrile). 18.4 mg (32% of theory, 100% purity) ofthe title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: −0.008 (3.27), 0.008 (2.98), 1.381(15.90), 1.398 (16.00), 2.074 (0.99), 2.367 (1.03), 2.711 (1.03), 3.288(4.49), 3.329 (4.49), 3.348 (6.38), 3.368 (4.68), 3.576 (5.10), 3.592(4.33), 3.598 (6.22), 3.616 (3.43), 4.881 (1.12), 4.900 (1.64), 4.923(1.67), 4.941 (1.06), 7.546 (1.22), 7.554 (4.33), 7.569 (1.92), 7.576(8.05), 7.584 (1.92), 7.598 (4.42), 7.607 (1.31), 7.667 (6.64), 8.426(9.14), 8.449 (12.60), 8.541 (12.86), 8.557 (0.90), 8.563 (8.88), 8.993(12.99), 10.250 (4.75), 10.273 (4.52).

LC-MS (Method 1): R_(t)=1.00 min; MS (ESIpos): m/z=500 [M+H]⁺

Example 342N-[(1R)-1-Cyclopropyl-2,2,2-trifluoroethyl]-4-oxo-7-(2-oxoimidazolidin-1-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 150 mg (371 μmol) of the compound from Example 113Awere reacted with 78.2 mg (445 μmol) of(1R)-1-cyclopropyl-2,2,2-trifluoroethanamine hydrochloride in thepresence of 169 mg (445 μmol) of HATU and 160 μl (930 μmol) ofN,N-diisopropylethylamine in 5.0 ml of dimethylformamide. The mixturewas diluted with 1 ml of 1N aqueous hydrochloric acid and 1 ml ofdimethyl sulphoxide and the solution was purified by means ofpreparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm, solvent:acetonitrile/0.05% formic acid gradient; 0 to 3 min 10% acetonitrile, to35 min 90% acetonitrile and for a further 3 min 90% acetonitrile).Finally, the crude product was suspended in 20 ml of acetonitrile anddiluted with 100 ml of water. Acetonitrile was removed under reducedpressure, and the precipitate was filtered off with suction and driedunder high vacuum. 85.3 mg (44% of theory, 100% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.341 (2.94), 0.354 (2.82), 0.576(3.29), 0.657 (2.82), 1.217 (2.63), 1.238 (2.90), 2.327 (2.08), 2.670(2.20), 2.710 (1.65), 3.349 (6.98), 3.370 (5.25), 3.578 (5.57), 3.599(7.10), 3.617 (3.76), 4.395 (2.39), 4.414 (2.55), 7.553 (5.18), 7.575(9.37), 7.597 (5.22), 7.669 (7.69), 8.430 (8.67), 8.453 (11.45), 8.552(11.92), 8.575 (8.04), 8.988 (16.00), 10.340 (5.33), 10.363 (5.37).

LC-MS (Method 1): R_(t)=1.03 min; MS (ESIpos): m/z=526 [M+H]⁺

Example 3434-Oxo-7-(2-oxoimidazolidin-1-yl)-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 100 mg (216 μmol) of the compound from Example 115Awere reacted with 186 mg (2.16 mmol) of imidazolidin-2-one in thepresence of 44.7 mg (323 μmol) of potassium carbonate, 4.8 mg (22 μmol)of palladium(II) acetate and 25.0 mg (43.1 μmol) of Xantphos in 2.2 mlof 1,4-dioxane. 100 mg of N-acetylcysteine were added and the mixturewas stirred at RT for 30 min. The reaction mixture was admixed with 30ml of ethyl acetate, washed with saturated aqueous sodiumhydrogencarbonate solution, dried over magnesium sulphate, filtered andconcentrated. The residue was purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient; 0 to 3 min 10% acetonitrile, to 35 min 90%acetonitrile and for a further 3 min 90% acetonitrile). Productfractions that were still contaminated were concentrated and repurifiedby means of normal phase chromatography (cyclohexane-ethyl acetategradient). The product fractions from the two separations were combinedand 46.6 mg (42% of theory, 100% purity) of the title compound wereobtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: −0.008 (2.95), 0.008 (2.68), 0.960(7.15), 0.978 (16.00), 0.997 (7.87), 1.148 (0.85), 1.623 (1.07), 1.641(1.56), 1.648 (1.70), 1.658 (1.74), 1.666 (1.61), 1.676 (1.56), 1.683(1.70), 1.701 (1.30), 1.862 (1.25), 1.872 (1.52), 1.881 (1.43), 1.890(1.74), 1.897 (1.52), 1.906 (1.21), 1.915 (1.16), 2.367 (1.39), 2.670(0.76), 2.710 (1.39), 3.287 (7.51), 3.330 (4.83), 3.350 (6.53), 3.370(5.05), 3.578 (5.27), 3.600 (6.75), 3.618 (3.80), 4.746 (1.39), 7.556(4.74), 7.578 (8.45), 7.600 (4.69), 7.668 (7.28), 8.429 (9.97), 8.452(13.27), 8.549 (13.77), 8.571 (9.34), 8.996 (15.28), 10.199 (5.14),10.223 (4.87).

LC-MS (Method 1): R_(t)=1.02 min; MS (ESIpos): m/z=514 [M+H]⁺

Example 3441-(2,4-Difluorophenyl)-7-(3-ethyl-2-oxotetrahydropyrimidin-1(2H)-yl)-4-oxo-N-[(2R)-1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 200 mg (449 μmol) of the compound from Example 67Awere reacted with 63.3 mg (494 μmol) of1-ethyltetrahydropyrimidin-2(1H)-one in the presence of 93.0 mg (673μmol) of potassium carbonate, 5.0 mg (22 μmol) of palladium(III) acetateand 26.0 mg (44.9 μmol) of Xantphos in 4.0 ml of 1,4-dioxane.Subsequently, the reaction mixture was acidified with aqueous 1Nhydrochloric acid and concentrated. The residue was dissolved in 10 mlof dichloromethane and purified by means of normal phase chromatography(cyclohexane-ethyl acetate gradient). 191.2 mg (76% of theory, 96%purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]=10.29 (d, 1H), 8.81-8.78 (m, 1H), 8.50(d, 1H), 8.15 (d, 1H), 7.91-7.83 (m, 1H), 7.65-7.57 (m, 1H), 7.39-7.32(m, 1H), 4.83-4.70 (m, 1H), 3.58-3.43 (m, 2H), 3.30-3.27 (m, 4H, partlyunder the water resonance), 1.95-1.83 (m, 3H), 1.72-1.60 (m, 1H), 1.07(t, 3H), 0.98 (t, 3H).

LC-MS (Method 3): R_(t)=2.22 min; MS (ESIpos): m/z=538 [M+H]⁺

Example 345 N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-1-(2,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP3, 50.0 mg (109 μmol) of the compound from Example 104Awere reacted with 16.8 mg (120 μmol) of (3R,4R)-pyrrolidine-3,4-diolhydrochloride in the presence of 67.0 μl (380 μmol) ofN,N-diisopropylethylamine in 2.0 ml of dimethylformamide. The reactionmixture was adjusted to pH 1 with aqueous 1 M hydrochloric acid andseparated by means of preparative HPLC (column: Chromatorex C18, 10 μm,125×30 mm, solvent: acetonitrile/0.05% formic acid gradient (0 to 3 min10% acetonitrile, to 35 min 90% acetonitrile and for a further 3 min 90%acetonitrile). The product fractions were combined and concentrated.50.9 mg (89% of theory, 100% purity) of the title compound wereobtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: −0.149 (0.90), −0.011 (4.62), −0.008(11.14), 0.008 (6.98), 0.146 (0.94), 0.316 (0.83), 0.327 (1.80), 0.338(2.71), 0.350 (2.71), 0.362 (2.01), 0.373 (1.04), 0.498 (0.83), 0.510(1.94), 0.522 (2.81), 0.534 (2.50), 0.549 (2.22), 0.557 (2.12), 0.569(2.85), 0.579 (2.36), 0.589 (2.15), 0.600 (1.77), 0.614 (1.15), 0.627(1.46), 0.637 (1.77), 0.648 (2.46), 0.652 (2.05), 0.658 (2.29), 0.663(2.22), 0.672 (2.15), 0.680 (1.01), 0.684 (0.94), 0.693 (0.69), 1.179(1.28), 1.188 (1.77), 1.200 (2.98), 1.208 (2.12), 1.212 (1.84), 1.220(2.85), 1.232 (1.49), 1.241 (1.04), 2.367 (1.11), 2.710 (1.11), 3.010(3.12), 3.042 (4.13), 3.174 (2.53), 3.184 (2.81), 3.206 (2.05), 3.216(1.77), 3.288 (7.05), 3.347 (3.85), 3.592 (2.29), 3.602 (2.53), 3.620(2.08), 3.630 (1.84), 3.893 (3.68), 4.039 (3.71), 4.356 (1.49), 4.376(2.39), 4.399 (2.33), 4.419 (1.28), 5.125 (5.48), 5.134 (5.34), 5.219(5.55), 5.228 (5.24), 6.769 (9.65), 6.792 (9.75), 7.395 (5.17), 7.415(10.72), 7.437 (5.83), 7.672 (1.15), 7.687 (2.33), 7.693 (2.19), 7.703(1.70), 7.709 (3.99), 7.714 (1.53), 7.725 (1.98), 7.731 (2.05), 7.746(0.94), 8.278 (12.08), 8.300 (11.04), 8.742 (16.00), 10.573 (5.93),10.596 (5.55).

LC-MS (Method 3): R_(t)=1.67 min; MS (ESIpos): m/z=525 [M+H]⁺

Example 3461-(2-Chloro-6-fluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-N-[(2S)-1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP3, 50.0 mg (108 μmol) of the compound from Example 119Aand 16.6 mg (119 μmol) of (3R,4R)-pyrrolidine-3,4-diol hydrochloridewere reacted in the presence of 53.0 μl (380 μmol) ofN,N-diisopropylethylamine in 1.0 ml of DMF. The reaction mixture wasadjusted to pH 1 with aqueous 1M hydrochloric acid and separated bymeans of preparative HPLC (column: Chromatorex C18, 10 m, 125×30 mm,solvent: acetonitrile/0.05% formic acid gradient (0 to 3 min 10%acetonitrile, to 35 min 90% acetonitrile and for a further 3 min 90%acetonitrile). 46.1 mg (80% of theory, 99% purity) of the title compoundwere obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: −0.008 (1.98), 0.008 (1.84), 0.952(3.72), 0.963 (4.56), 0.971 (8.66), 0.981 (8.89), 0.989 (4.80), 1.000(4.09), 1.622 (0.99), 1.633 (1.04), 1.639 (1.46), 1.649 (1.32), 1.657(1.46), 1.668 (1.08), 1.674 (1.13), 1.854 (1.08), 1.864 (1.27), 1.871(1.32), 1.883 (1.46), 1.899 (1.18), 1.907 (0.94), 2.367 (1.08), 2.711(1.08), 2.950 (1.51), 2.980 (2.54), 3.007 (1.98), 3.124 (1.18), 3.133(1.46), 3.143 (1.32), 3.154 (1.98), 3.165 (1.04), 3.174 (1.04), 3.291(4.24), 3.339 (4.42), 3.585 (2.02), 3.595 (2.26), 3.612 (1.93), 3.623(1.69), 3.883 (3.34), 4.034 (3.34), 4.733 (1.36), 4.752 (1.27), 5.126(3.48), 5.130 (3.91), 5.135 (3.95), 5.222 (3.95), 5.227 (3.86), 6.762(8.52), 6.784 (8.75), 7.522 (1.08), 7.527 (1.79), 7.531 (1.27), 7.543(1.79), 7.547 (3.34), 7.551 (2.78), 7.566 (1.51), 7.570 (2.26), 7.575(1.60), 7.620 (2.26), 7.623 (2.35), 7.627 (1.27), 7.641 (4.80), 7.643(5.08), 7.647 (2.21), 7.665 (3.01), 7.680 (3.01), 7.686 (3.72), 7.700(3.76), 7.706 (1.46), 7.721 (1.36), 8.275 (9.88), 8.297 (9.27), 8.695(16.00), 10.458 (3.29), 10.462 (3.34), 10.482 (3.25), 10.486 (3.20).

LC-MS (Method 3): R_(t)=1.68 min; MS (ESIpos): m/z=529 [M+H]⁺

Example 347 1-(2-Chloro-6-fluorophenyl)-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP3, 50.0 mg (105 μmol) of the compound from Example 120Aand 16.2 mg (116 μmol) of (3R,4R)-pyrrolidine-3,4-diol hydrochloridewere reacted in the presence of 52.0 μl (370 μmol) ofN,N-diisopropylethylamine in 1.0 ml of DMF. The reaction mixture wasadjusted to pH 1 with aqueous 1N hydrochloric acid and purified by meansof preparative HPLC (column: Chromatorex C18, 10 m, 125×30 mm, solvent:acetonitrile/0.05% formic acid gradient (0 to 3 min 10% acetonitrile, to35 min 90% acetonitrile and for a further 3 min 90% acetonitrile). 48.3mg (84% of theory, 99% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]=10.61 (d, 1H), 8.69 (s, 1H), 8.29 (d,1H), 7.73-7.51 (m, 3H), 6.77 (d, 1H), 5.24-5.20 (m, 1H), 5.14-5.11 (m,1H), 4.43-4.32 (m, 1H), 4.03 (br. s, 1H), 3.88 (br. s, 1H), 3.64-3.56(m, 1H), 3.20-3.10 (m, 1H), 3.02-2.93 (m, 1H), 1.26-1.16 (m, 1H),0.71-0.47 (m, 3H), 0.39-0.29 (m, 1H).

LC-MS (Method 3): R_(t)=1.72 min; MS (ESIpos): m/z=541 [M+H]⁺

Example 3481-(2,6-Difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP3, 50.0 mg (111 μmol) of the compound from Example 114Awere reacted with 17.0 mg (122 μmol) of (3R,4R)-pyrrolidine-3,4-diolhydrochloride in the presence of 68.0 μl (390 μmol) ofN,N-diisopropylethylamine in 1.1 ml of dimethylformamide. The reactionmixture was diluted with 2 ml of acetonitrile, acidified with 1N aqueoushydrochloric acid and purified by means of preparative HPLC (column:Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05% formicacid gradient; 0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrileand for a further 3 min 90% acetonitrile). 50.9 mg (89% of theory, 100%purity) of the title compound were obtained.

¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 0.960 (7.49), 0.974 (16.00), 0.989(7.72), 1.614 (1.16), 1.629 (1.43), 1.634 (1.34), 1.642 (1.76), 1.649(1.57), 1.657 (1.48), 1.662 (1.62), 1.677 (1.25), 1.859 (1.29), 1.867(1.48), 1.874 (1.48), 1.882 (1.66), 1.887 (1.48), 1.894 (1.29), 1.902(1.16), 1.909 (0.97), 3.017 (2.82), 3.043 (3.61), 3.180 (2.13), 3.188(2.36), 3.205 (1.76), 3.213 (1.57), 3.344 (3.75), 3.596 (1.99), 3.603(2.22), 3.618 (1.90), 3.626 (1.66), 3.895 (3.24), 4.043 (3.24), 4.735(1.29), 4.743 (1.20), 5.130 (4.21), 5.137 (4.21), 5.226 (4.16), 5.233(3.93), 6.771 (8.92), 6.789 (9.02), 7.402 (3.47), 7.419 (6.94), 7.437(3.61), 7.682 (0.88), 7.694 (1.85), 7.699 (1.90), 7.707 (1.43), 7.712(3.28), 7.716 (1.29), 7.724 (1.76), 7.729 (1.71), 7.741 (0.79), 8.278(11.05), 8.296 (10.27), 8.751 (15.72), 10.442 (5.18), 10.462 (4.90).

LC-MS (Method 1): R_(t)=1.63 min; MS (ESIpos): m/z=513 [M+H]⁺

Example 3497-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 55.0 mg (131 μmol) of the compound from Example 121Awere reacted with 24.3 mg (157 μmol) of(2R)-1,1,1-trifluoro-3,3-dimethylbutan-2-amine in the presence of 74.5mg (196 μmol) of HATU and 57.0 μl (330 μmol) ofN,N-diisopropylethylamine in 2.0 ml of dimethylformamide. The mixturewas diluted with 1 ml of water and 2 ml of acetonitrile and the solutionwas purified by means of preparative HPLC (column: Chromatorex C18, 10μm, 125×30 mm, solvent: acetonitrile/0.05% formic acid gradient; 0 to 3min 10% acetonitrile, to 35 min 90% acetonitrile and for a further 3 min90% acetonitrile). 55.9 mg (77% of theory, 100% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: −0.008 (0.77), 0.008 (0.71), 1.090(16.00), 3.057 (0.73), 3.089 (0.96), 3.241 (0.64), 3.289 (0.78), 3.331(0.87), 3.360 (0.89), 3.611 (0.58), 3.931 (0.86), 4.050 (0.86), 4.622(0.74), 5.145 (1.36), 5.154 (1.36), 5.229 (1.36), 5.238 (1.34), 6.771(2.11), 6.793 (2.16), 7.544 (0.97), 7.567 (1.61), 7.587 (0.93), 8.297(2.61), 8.319 (2.43), 8.816 (4.01), 10.765 (1.26), 10.790 (1.19).

LC-MS (Method 3): R_(t)=1.86 min; MS (ESIpos): m/z=559 [M+H]⁺

Example 3507-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-4-oxo-N-[1-(trifluoromethyl)cyclopentyl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 55.0 mg (131 μmol) of the compound from Example 121Awere reacted with 29.7 mg (157 μmol) of1-(trifluoromethyl)cyclopentanamine hydrochloride in the presence of74.5 mg (196 μmol) of HATU and 79.6 μl (460 μmol) ofN,N-diisopropylethylamine in 2.0 ml of dimethylformamide. The mixturewas diluted with 1 ml of water and 2 ml of acetonitrile and the solutionwas purified by means of preparative HPLC (column: Chromatorex C18, 10μm, 125×30 mm, solvent: acetonitrile/0.05% formic acid gradient; 0 to 3min 10% acetonitrile, to 35 min 90% acetonitrile and for a further 3 min90% acetonitrile). 63.4 mg (87% of theory, 100% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: −0.008 (4.57), 0.008 (4.33), 1.708(1.76), 1.729 (3.67), 1.747 (3.47), 1.765 (3.35), 1.784 (3.71), 1.794(3.02), 1.803 (3.27), 1.824 (1.96), 2.012 (1.84), 2.029 (3.10), 2.045(3.63), 2.063 (3.67), 2.073 (16.00), 2.079 (2.12), 2.353 (2.61), 2.367(4.73), 2.382 (2.90), 2.400 (2.82), 2.711 (1.43), 3.052 (3.14), 3.083(4.20), 3.225 (2.37), 3.235 (2.73), 3.256 (2.04), 3.267 (1.96), 3.288(4.53), 3.349 (4.08), 3.593 (2.20), 3.603 (2.57), 3.621 (2.08), 3.632(1.92), 3.926 (3.76), 4.046 (3.76), 5.135 (5.67), 5.144 (5.76), 5.227(5.76), 5.236 (5.67), 6.760 (9.55), 6.782 (9.76), 7.541 (2.61), 7.545(2.94), 7.553 (1.96), 7.561 (5.02), 7.564 (5.02), 7.567 (5.14), 7.576(2.00), 7.584 (3.02), 7.599 (0.98), 8.263 (11.02), 8.286 (10.49), 8.741(15.39), 10.513 (11.71).

LC-MS (Method 3): R_(t)=1.83 min; MS (ESIpos): m/z=557 [M+H]⁺

Example 3511-(2-Chloro-6-fluorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 100 mg (216 μmol) of the compound from Example 119Awere reacted with 24.1 mg (238 μmol) of (4S)-4-hydroxypyrrolidin-2-onein the presence of 44.8 mg (325 μmol) of potassium carbonate, 2.4 mg (11μmol) of palladium(II) acetate and 12.5 mg (21.6 μmol) of Xantphos in1.9 ml of 1,4-dioxane. Subsequently, 100 mg of N-acetylcysteine wereadded and the mixture was stirred at RT for a further 0.5 h. Afteradding 20 ml of ethyl acetate, the mixture was extracted with saturatedaqueous sodium hydrogencarbonate solution. The organic phase wasconcentrated and the residue was purified by means of preparative HPLC(column: Chromatorex C18, 10 m, 125×30 mm, eluent: acetonitrile/0.05%formic acid gradient; 0 to 3 min 10% acetonitrile, to 35 min 90%acetonitrile and for a further 3 min 90% acetonitrile). 54.1 mg (47% oftheory, 98% purity) of the title compound were obtained.

¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 0.968 (5.41), 0.979 (6.69), 0.983(11.85), 0.993 (10.59), 0.998 (6.60), 1.008 (4.54), 1.643 (0.88), 1.654(1.09), 1.657 (1.29), 1.663 (1.13), 1.670 (1.71), 1.674 (1.40), 1.678(1.37), 1.682 (1.45), 1.685 (1.54), 1.688 (1.55), 1.691 (1.52), 1.696(1.13), 1.702 (1.30), 1.705 (1.14), 1.717 (0.85), 1.876 (1.21), 1.883(1.40), 1.886 (1.47), 1.891 (1.56), 1.898 (1.66), 1.902 (1.71), 1.906(1.44), 1.911 (1.53), 1.918 (1.18), 1.921 (0.99), 1.926 (0.88), 2.076(0.84), 2.345 (3.82), 2.348 (3.60), 2.380 (4.31), 2.383 (4.02), 2.909(4.60), 2.920 (4.73), 2.943 (4.34), 2.955 (4.16), 3.354 (3.09), 3.377(5.05), 3.401 (2.58), 3.572 (2.04), 3.581 (2.57), 3.590 (2.42), 3.595(2.49), 3.600 (3.01), 3.605 (1.86), 3.614 (2.31), 3.624 (1.88), 4.249(3.61), 4.767 (1.64), 4.777 (1.52), 5.327 (1.59), 7.572 (1.57), 7.574(1.63), 7.586 (1.95), 7.589 (3.77), 7.591 (3.44), 7.603 (2.47), 7.607(3.70), 7.610 (2.16), 7.621 (1.59), 7.624 (1.62), 7.661 (2.54), 7.663(1.64), 7.675 (4.62), 7.677 (5.15), 7.680 (2.34), 7.691 (4.43), 7.693(2.60), 7.724 (3.27), 7.736 (3.47), 7.741 (4.77), 7.753 (4.66), 7.758(2.03), 7.769 (1.86), 8.532 (11.77), 8.550 (13.29), 8.722 (13.08), 8.740(10.70), 8.796 (0.68), 8.992 (14.83), 8.994 (16.00), 10.136 (3.78),10.140 (4.00), 10.155 (3.69), 10.159 (3.79).

LC-MS (Method 1): R_(t)=1.00 min; MS (ESIpos): m/z=527 [M+H]⁺

Example 3521-(2-Chloro-6-fluorophenyl)-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 100 mg (211 μmol) of the compound from Example 120Awere reacted with 23.5 mg (232 μmol) of (4S)-4-hydroxypyrrolidin-2-onein the presence of 43.7 mg (316 μmol) of potassium carbonate, 2.4 mg (11μmol) of palladium(II) acetate and 12.2 mg (21.1 μmol) of Xantphos in1.9 ml of 1,4-dioxane. Subsequently, 100 mg of N-acetylcysteine wereadded and the mixture was stirred at RT for a further 0.5 h. Afteradding 20 ml of ethyl acetate, the mixture was extracted with saturatedaqueous sodium hydrogencarbonate solution. The organic phase wasconcentrated and the residue was purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient; 0 to 3 min 10% acetonitrile, to 35 min 90%acetonitrile and for a further 3 min 90% acetonitrile). 63.8 mg (56% oftheory, 99% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: −0.149 (0.89), −0.008 (7.91), 0.008(7.20), 0.146 (0.94), 0.343 (2.06), 0.356 (2.46), 0.368 (1.92), 0.379(1.30), 0.549 (2.06), 0.563 (2.91), 0.578 (2.77), 0.588 (2.55), 0.598(1.92), 0.608 (1.65), 0.622 (1.07), 0.638 (0.85), 0.648 (1.34), 0.659(1.70), 0.669 (2.10), 0.684 (1.52), 0.689 (1.16), 1.208 (0.89), 1.215(1.12), 1.227 (2.10), 1.248 (2.06), 1.260 (1.12), 2.337 (3.44), 2.366(1.65), 2.380 (3.71), 2.670 (0.63), 2.710 (1.52), 2.899 (3.49), 2.914(3.58), 2.942 (3.13), 2.957 (3.08), 3.287 (5.45), 3.345 (2.32), 3.374(2.95), 3.398 (1.83), 3.563 (1.34), 3.574 (1.83), 3.582 (2.01), 3.593(3.22), 3.605 (1.25), 3.611 (1.88), 3.624 (1.56), 4.239 (2.59), 4.382(1.30), 4.402 (1.79), 4.420 (1.52), 5.318 (7.60), 5.327 (7.37), 7.563(1.21), 7.567 (1.39), 7.576 (1.07), 7.579 (1.21), 7.587 (2.82), 7.599(2.06), 7.607 (1.79), 7.610 (1.79), 7.623 (1.25), 7.654 (1.61), 7.665(2.23), 7.669 (1.70), 7.675 (2.91), 7.686 (4.07), 7.689 (2.46), 7.715(2.99), 7.729 (3.13), 7.736 (4.07), 7.750 (3.89), 7.757 (1.65), 7.771(1.47), 8.529 (9.25), 8.551 (10.99), 8.722 (11.22), 8.744 (8.98), 8.984(16.00), 10.277 (4.83), 10.301 (4.65).

LC-MS (Method 3): R_(t)=1.05 min; MS (ESIpos): m/z=539 [M+H]⁺

Example 3537-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-4-oxo-N-[(2S)-1-(trifluoromethoxy)propan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP3, 50.0 mg (104 μmol) of the compound from Example 118Awere reacted with 16.0 mg (115 μmol) of (3R,4R)-pyrrolidine-3,4-diolhydrochloride in the presence of 63.5 μl (365 μmol) ofN,N-diisopropylethylamine in 1.0 ml of dimethylformamide. The reactionmixture was diluted with 2 ml of acetonitrile, acidified with aqueous 1Nhydrochloric acid and purified by means of preparative HPLC (column:Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05% formicacid gradient; 0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrileand for a further 3 min 90% acetonitrile). 47.9 mg (84% of theory, 100%purity) of the title compound were obtained.

¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.244 (16.00), 1.258 (15.83), 2.073(7.16), 3.057 (2.15), 3.082 (2.68), 3.229 (1.66), 3.237 (1.86), 3.254(1.49), 3.262 (1.42), 3.338 (3.21), 3.596 (1.49), 3.604 (1.66), 3.618(1.42), 3.626 (1.26), 3.925 (2.55), 4.047 (2.55), 4.139 (0.89), 4.149(1.29), 4.159 (4.41), 4.167 (7.16), 4.176 (4.90), 4.186 (1.03), 4.196(1.09), 4.316 (0.70), 4.325 (1.23), 4.339 (1.62), 4.354 (1.13), 5.137(3.41), 5.144 (3.38), 5.226 (3.35), 5.234 (3.25), 6.747 (6.92), 6.765(6.96), 7.539 (1.89), 7.543 (2.09), 7.555 (3.48), 7.561 (3.54), 7.567(1.62), 7.573 (2.09), 7.578 (1.76), 8.260 (8.68), 8.278 (8.08), 8.722(12.99), 10.091 (4.07), 10.107 (3.84).

LC-MS (Method 3): R_(t)=1.63 min; MS (ESIpos): m/z=547 [M+H]⁺

Example 3541-(2,4-Difluorophenyl)-7-[1-hydroxy-3-azabicyclo[4.1.0]hept-3-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP3, 50.0 mg (112 μmol) of the compound from Example 67Awere reacted with 21.2 mg (95% purity, 135 μmol) of5-azaspiro[2.4]heptan-7-ol hydrochloride in the presence of 68.0 μl (390μmol) of N,N-diisopropylethylamine in 0.5 ml of dimethylformamide. Thereaction mixture was diluted with 1 ml of acetonitrile and 0.1 ml of 1Naqueous hydrochloric acid and purified by means of preparative HPLC(column: Chromatorex C18, 10 m, 125×30 mm, solvent: acetonitrile/0.1%formic acid gradient; 0 to 5 min 10% acetonitrile, over 14 min to 90%acetonitrile and for a further 4 min 90% acetonitrile). 49.9 mg (84% oftheory, 99% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: −0.011 (2.18), −0.008 (5.18), 0.008(3.42), 0.146 (0.60), 0.178 (1.43), 0.204 (1.20), 0.219 (1.62), 0.232(0.90), 0.666 (1.84), 0.679 (1.99), 0.690 (2.10), 0.704 (1.77), 0.945(7.51), 0.963 (16.00), 0.982 (7.70), 1.101 (1.92), 1.110 (1.77), 1.119(1.80), 1.477 (1.01), 1.596 (1.20), 1.614 (1.54), 1.621 (1.43), 1.630(1.88), 1.639 (1.65), 1.649 (1.58), 1.656 (1.73), 1.674 (1.28), 1.848(1.35), 1.858 (1.62), 1.867 (1.58), 1.877 (1.77), 1.883 (1.58), 1.893(1.39), 1.902 (1.24), 1.912 (1.13), 1.966 (1.05), 2.367 (1.28), 2.478(1.95), 2.519 (3.15), 2.523 (3.64), 2.710 (1.20), 3.103 (0.79), 3.288(5.07), 3.384 (1.77), 3.399 (1.50), 3.416 (1.50), 4.013 (2.85), 4.046(2.55), 4.730 (1.46), 4.751 (1.31), 5.603 (2.70), 6.978 (2.74), 7.001(2.74), 7.309 (1.46), 7.331 (2.63), 7.352 (1.39), 7.544 (1.50), 7.550(1.58), 7.569 (2.52), 7.573 (2.48), 7.592 (1.46), 7.599 (1.35), 7.805(1.80), 7.814 (1.69), 7.828 (1.69), 8.267 (10.07), 8.290 (9.31), 8.613(7.25), 10.467 (5.07), 10.491 (4.77).

LC-MS (Method 3): R_(t)=2.02 min; MS (ESIpos): m/z=523 [M+H]⁺

Example 3551-(2,4-Difluorophenyl)-7-[7-hydroxy-5-azaspiro[2.4]hept-5-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP3, 50.0 mg (112 μmol) of the compound from Example 67Awere reacted with 21.2 mg (95% purity, 135 μmol) of3-azabicyclo[4.1.0]heptan-1-ol hydrochloride in the presence of 68.0 μl(393 μmol) of N,N-diisopropylethylamine in 0.5 ml of dimethylformamide.The reaction mixture was diluted with 1 ml of acetonitrile and 0.1 ml of1N aqueous hydrochloric acid and purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.1%formic acid gradient; 0 to 5 min 10% acetonitrile, over 14 min to 90%acetonitrile and for a further 4 min 90% acetonitrile). 48.8 mg (82% oftheory, 99% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: −0.008 (3.32), 0.008 (3.21), 0.470(1.19), 0.585 (4.12), 0.818 (1.66), 0.949 (7.22), 0.968 (16.00), 0.986(7.77), 1.598 (1.12), 1.616 (1.44), 1.624 (1.34), 1.633 (1.77), 1.642(1.63), 1.651 (1.52), 1.659 (1.73), 1.677 (1.30), 1.850 (1.30), 1.860(1.52), 1.869 (1.52), 1.879 (1.73), 1.885 (1.52), 1.895 (1.30), 1.904(1.16), 1.913 (0.98), 2.367 (1.23), 2.563 (1.05), 2.711 (1.26), 3.168(0.87), 3.202 (1.12), 3.228 (1.08), 3.288 (3.36), 3.298 (2.93), 3.334(1.52), 3.344 (1.34), 3.355 (1.26), 3.624 (1.59), 3.668 (1.08), 3.741(1.16), 4.734 (1.34), 4.753 (1.30), 4.942 (0.76), 4.987 (0.79), 6.655(1.48), 6.677 (1.55), 6.776 (0.79), 6.798 (0.76), 7.326 (1.55), 7.571(1.23), 7.812 (1.52), 8.277 (4.19), 8.300 (4.05), 8.614 (2.96), 10.504(5.24), 10.528 (5.06).

LC-MS (Method 3): R_(t)=2.05 min; MS (ESIpos): m/z=523 [M+H]⁺

Example 3561-(2,4-Difluorophenyl)-7-[4-hydroxy-3,3-dimethylpyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP3, 50.0 mg (112 μmol) of the compound from Example 67Awere reacted with 21.5 mg (95% purity, 135 μmol) of4,4-dimethylpyrrolidin-3-ol hydrochloride in the presence of 68.0 μl(393 μmol) of N,N-diisopropylethylamine in 0.5 ml of dimethylformamide.The reaction mixture was diluted with 1 ml of acetonitrile and 0.1 ml of1N aqueous hydrochloric acid and purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.1%formic acid gradient; 0 to 5 min 10% acetonitrile, over 14 min to 90%acetonitrile and for a further 4 min 90% acetonitrile). 52.4 mg (88% oftheory, 99% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]=10.51 (d, 1H), 8.60 (s, 1H), 8.27 (d,1H), 7.86-7.76 (m, 1H), 7.63-7.56 (m, 1H), 7.37-7.29 (m, 1H), 6.73 (d,1H), 5.21-5.00 (m, 1H), 4.81-4.67 (m, 1H), 3.86-3.64 (m, 1.5H),3.07-2.82 (m, 1.5H), 1.93-1.82 (m, 1H), 1.70-1.57 (m, 1H), 1.04-0.84 (m,9H), 2H under the water signal.

LC-MS (Method 3): R_(t)=2.13 min; MS (ESIpos): m/z=525 [M+H]⁺

Example 3577-[(4S)-4-Hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 50.0 mg (119 μmol) of the compound from Example 117Awere reacted with 22.2 mg (143 μmol) of(2R)-1,1,1-trifluoro-3,3-dimethylbutan-2-amine in the presence of 68.0mg (179 μmol) of HATU and 41.5 μl (240 μmol) ofN,N-diisopropylethylamine in 1.2 ml of dimethylformamide. The reactionmixture was diluted with 2 ml of acetonitrile and 1 ml of water andpurified by means of preparative HPLC (column: Chromatorex C18, 10 μm,125×30 mm, solvent: acetonitrile/0.1% formic acid gradient; 0 to 5 min10% acetonitrile, over 14 min to 90% acetonitrile and for a further 4min 90% acetonitrile). 56.2 mg (84% of theory, 99% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: −0.008 (0.93), 0.008 (0.57), 1.103(16.00), 2.358 (0.92), 2.401 (1.06), 2.918 (0.90), 2.933 (0.92), 2.961(0.82), 2.976 (0.78), 3.289 (1.34), 3.465 (0.91), 3.495 (1.09), 3.674(0.83), 3.686 (0.99), 3.704 (0.76), 3.716 (0.65), 4.291 (0.70), 4.300(0.67), 4.626 (0.57), 4.651 (0.73), 5.336 (2.14), 5.345 (2.04), 7.596(0.65), 7.601 (0.72), 7.616 (1.15), 7.624 (1.13), 7.639 (0.68), 8.535(3.00), 8.557 (3.38), 8.739 (3.49), 8.761 (2.76), 9.087 (3.75), 10.467(1.27), 10.492 (1.18).

LC-MS (Method 3): R_(t)=2.05 min; MS (ESIpos): m/z=557 [M+H]⁺

Example 358N-(Bicyclo[1.1.1]pent-1-yl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 45.0 mg (107 μmol) of the compound from Example 117Awere reacted with 15.4 mg (129 μmol) of bicyclo[1.1.1]pentan-1-aminehydrochloride in the presence of 61.2 mg (161 μmol) of HATU and 37.4 μl(210 μmol) of N,N-diisopropylethylamine in 2.0 ml of dimethylformamide.The reaction mixture was diluted with 2 ml of acetonitrile and 1 ml ofwater and purified by means of preparative HPLC (column: ChromatorexC18, 10 μm, 125×30 mm, solvent: acetonitrile/0.1% formic acid gradient;0 to 5 min 10% acetonitrile, over 14 min to 90% acetonitrile and for afurther 4 min 90% acetonitrile). 31.9 mg (61% of theory, 100% purity) ofthe title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.113 (16.00), 2.392 (0.81), 2.910(0.63), 2.925 (0.66), 3.456 (0.70), 3.486 (0.85), 3.678 (0.73), 5.326(0.89), 5.335 (0.88), 8.505 (1.28), 8.527 (1.65), 8.663 (1.35), 8.665(1.49), 8.687 (1.16), 8.927 (2.46), 10.002 (1.75).

LC-MS (Method 3): R_(t)=1.76 min; MS (ESIpos): m/z=485 [M+H]⁺

Example 3594-Oxo-7-(2-oxoimidazolidin-1-yl)-N-[(2S)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 30.0 mg (74.2 μmol) of the compound from Example 113Awere reacted with 13.8 mg (89.0 μmol) of(2S)-1,1,1-trifluoro-3,3-dimethylbutan-2-amine in the presence of 33.9mg (89.0 μmol) of HATU and 32.0 μl (190 μmol) ofN,N-diisopropylethylamine in 1.0 ml of dimethylformamide. The reactionmixture was diluted with 2 ml of DMSO, water and 1 ml of aqueous 1Nhydrochloric acid and purified by means of preparative HPLC (column:Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.1% formicacid gradient; 0 to 5 min 10% acetonitrile, over 14 min to 90%acetonitrile and for a further 4 min 90% acetonitrile). 31.5 mg (78% oftheory, 99% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.098 (16.00), 3.351 (1.68), 3.372(1.25), 3.581 (1.30), 3.597 (1.13), 3.602 (1.65), 3.621 (0.93), 4.642(0.74), 7.556 (1.06), 7.578 (1.77), 7.599 (1.05), 7.674 (1.85), 8.434(2.49), 8.456 (3.12), 8.581 (3.18), 8.603 (2.40), 9.009 (3.62), 10.558(1.22), 10.584 (1.17).

LC-MS (Method 3): R_(t)=2.12 min; MS (ESIpos): m/z=542 [M+H]⁺

Example 3604-Oxo-7-(2-oxoimidazolidin-1-yl)-N-[(2S)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 30.0 mg (74.2 μmol) of the compound from Example 113Awere reacted with 13.8 mg (89.0 μmol) of(2R)-1,1,1-trifluoro-3,3-dimethylbutan-2-amine in the presence of 33.9mg (89.0 μmol) of HATU and 32.0 μl (190 μmol) ofN,N-diisopropylethylamine in 1.0 ml of dimethylformamide. The reactionmixture was diluted with 2 ml of DMSO, water and 1 ml of aqueous 1Nhydrochloric acid and purified by means of preparative HPLC (column:Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.1% formicacid gradient; 0 to 5 min 10% acetonitrile, over 14 min to 90%acetonitrile and for a further 4 min 90% acetonitrile). 33.2 mg (82% oftheory, 99% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: −0.008 (0.92), 0.008 (0.92), 1.098(16.00), 3.351 (1.77), 3.371 (1.30), 3.580 (1.30), 3.596 (1.15), 3.601(1.65), 3.620 (0.92), 4.641 (0.74), 7.555 (1.03), 7.578 (1.74), 7.599(1.00), 7.673 (1.83), 8.433 (2.33), 8.455 (2.98), 8.580 (2.95), 8.603(2.27), 9.009 (3.42), 10.558 (1.21), 10.583 (1.15).

LC-MS (Method 3): R_(t)=2.13 min; MS (ESIpos): m/z=542 [M+H]⁺

Example 3617-[3-(2-Hydroxyethyl)-2-oxoimidazolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 30 mg (67 μmol) of the compound from Example 123A werereacted with 12.5 mg (80.3 μmol) of(2R)-1,1,1-trifluoro-3,3-dimethylbutan-2-amine in the presence of 30.5mg (80.3 μmol) of HATU and 29 μl (0.17 mmol) ofN,N-diisopropylethylamine in 1.0 ml of dimethylformamide. The reactionmixture was diluted with 2 ml of DMSO, water and 1 ml of aqueous 1Nhydrochloric acid and purified by means of preparative HPLC (column:Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.1% formicacid gradient; 0 to 5 min 10% acetonitrile, over 14 min to 90%acetonitrile and for a further 4 min 90% acetonitrile). 33.3 mg (85% oftheory, 100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.098 (16.00), 3.260 (1.13), 3.275(2.52), 3.288 (1.60), 3.490 (1.10), 3.505 (2.50), 3.519 (2.79), 3.526(2.42), 3.533 (2.77), 3.545 (1.40), 4.641 (0.73), 4.727 (0.93), 4.741(2.09), 4.755 (0.89), 7.558 (1.06), 7.580 (1.87), 7.602 (1.03), 8.437(2.12), 8.459 (2.61), 8.594 (2.67), 8.616 (1.99), 9.009 (3.66), 10.554(1.19), 10.579 (1.13).

LC-MS (Method 3): R_(t)=2.03 min; MS (ESIpos): m/z=586 [M+H]⁺

Example 3627-[3-(2-Hydroxyethyl)-2-oxoimidazolidin-1-yl]-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 30 mg (67 μmol) of the compound from Example 123A werereacted with 13.1 mg (80.3 μmol) of (2S)-1,1,1-trifluorobutan-2-aminehydrochloride in the presence of 38.2 mg (100 μmol) of HATU and 29 μl(0.17 mmol) of N,N-diisopropylethylamine in 1.0 ml of dimethylformamide.The mixture was diluted with 1 ml of water and 2 ml of acetonitrile andthe solution was purified by means of preparative HPLC (column:Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.1% formicacid gradient; 0 to 5 min 10% acetonitrile, over 14 min to 90%acetonitrile and for a further 4 min 90% acetonitrile). 33.3 mg (89% oftheory, 100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: −0.008 (2.42), 0.008 (2.11), 0.959(7.16), 0.978 (16.00), 0.996 (7.76), 1.624 (1.00), 1.641 (1.49), 1.659(1.80), 1.684 (1.69), 1.702 (1.29), 1.881 (1.58), 1.891 (1.67), 1.915(1.27), 2.328 (1.22), 2.524 (3.47), 2.670 (1.36), 3.259 (4.78), 3.273(10.56), 3.287 (6.18), 3.489 (4.40), 3.504 (10.07), 3.518 (11.49), 3.524(9.87), 3.532 (11.36), 3.543 (5.64), 4.727 (4.56), 4.741 (9.96), 4.755(5.24), 7.558 (4.78), 7.581 (8.69), 7.603 (4.67), 8.434 (9.07), 8.456(11.67), 8.563 (12.18), 8.586 (8.51), 8.996 (15.76), 10.195 (5.09),10.219 (5.00).

LC-MS (Method 3): R_(t)=1.86 min; MS (ESIpos): m/z=558 [M+H]⁺

Example 363 N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[3-(2-hydroxyethyl)-2-oxoimidazolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 30.0 mg (66.9 μmol) of the compound from Example 123Awere reacted with 14.1 mg (80.3 μmol) of(1S)-1-cyclopropyl-2,2,2-trifluoroethanamine hydrochloride in thepresence of 38.2 mg (100 μmol) of HATU and 29 μl (0.17 mmol) ofN,N-diisopropylethylamine in 1.0 ml of dimethylformamide. The mixturewas diluted with 1 ml of water and 2 ml of acetonitrile and the solutionwas purified by means of preparative HPLC (column: Chromatorex C18, 10m, 125×30 mm, solvent: acetonitrile/0.1% formic acid gradient; 0 to 5min 10% acetonitrile, over 14 min to 90% acetonitrile and for a further4 min 90% acetonitrile). 30.9 mg (81% of theory, 100% purity) of thetitle compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: −0.008 (1.99), 0.008 (1.85), 0.331(2.01), 0.342 (3.30), 0.354 (3.18), 0.365 (2.27), 0.377 (1.33), 0.528(2.08), 0.540 (3.18), 0.553 (3.20), 0.559 (3.65), 0.564 (2.99), 0.577(3.84), 0.586 (2.81), 0.596 (2.55), 0.607 (2.06), 0.621 (1.24), 0.635(1.64), 0.645 (1.73), 0.656 (3.35), 0.659 (2.55), 0.666 (2.60), 0.672(2.22), 0.677 (2.25), 0.680 (2.04), 0.687 (1.19), 0.692 (1.29), 0.699(0.77), 1.199 (1.29), 1.207 (1.85), 1.220 (3.11), 1.228 (2.27), 1.240(3.09), 1.252 (1.68), 1.260 (1.15), 2.328 (0.80), 2.524 (2.85), 2.671(0.87), 3.260 (5.94), 3.274 (13.33), 3.288 (7.79), 3.463 (1.64), 3.478(2.60), 3.493 (5.80), 3.498 (5.57), 3.504 (12.91), 3.519 (14.90), 3.524(13.05), 3.532 (14.29), 3.542 (7.18), 3.547 (6.22), 3.566 (1.82), 4.372(1.61), 4.393 (2.83), 4.415 (2.78), 4.435 (1.50), 4.726 (4.35), 4.740(10.06), 4.754 (4.33), 7.547 (1.64), 7.555 (5.61), 7.570 (2.67), 7.578(10.74), 7.585 (2.90), 7.600 (5.68), 7.608 (1.85), 8.435 (10.50), 8.457(13.99), 8.567 (13.92), 8.590 (10.32), 8.988 (16.00), 10.336 (6.69),10.360 (6.41).

LC-MS (Method 3): R_(t)=1.88 min; MS (ESIpos): m/z=570 [M+H]⁺

Example 364 N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[3-(2-hydroxyethyl)-2-oxotetrahydropyrimidin-1(2H)-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 54 mg (78% purity, 91 μmol) of the compound fromExample 125A were reacted with 19.2 mg (109 μmol) of(1S)-1-cyclopropyl-2,2,2-trifluoroethanamine hydrochloride in thepresence of 41.6 mg (109 μmol) of HATU and 40 μl (0.23 mmol) ofN,N-diisopropylethylamine in 1.5 ml of dimethylformamide. The mixturewas diluted with 1 ml of aqueous 1N hydrochloric acid and 2 ml of DMSOand the solution was purified by means of preparative HPLC (column:Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.1% formicacid gradient; 0 to 5 min 10% acetonitrile, over 14 min to 90%acetonitrile and for a further 2 min 90% acetonitrile). 33.9 mg (63% oftheory, 99% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: −0.149 (0.60), −0.008 (6.40), 0.008(4.91), 0.146 (0.64), 0.333 (1.84), 0.343 (3.22), 0.355 (3.03), 0.366(2.03), 0.378 (1.34), 0.534 (1.96), 0.545 (2.95), 0.560 (3.80), 0.578(4.09), 0.588 (2.73), 0.599 (2.38), 0.609 (1.93), 0.623 (1.14), 0.637(1.49), 0.647 (1.71), 0.658 (3.30), 0.668 (2.51), 0.676 (2.16), 0.693(1.27), 1.187 (0.64), 1.200 (1.27), 1.208 (1.74), 1.220 (2.95), 1.229(2.16), 1.241 (2.85), 1.253 (1.51), 1.261 (1.09), 1.274 (0.47), 1.878(1.44), 1.893 (4.09), 1.907 (6.28), 1.922 (4.29), 1.937 (1.56), 2.001(0.64), 2.323 (1.04), 2.328 (1.44), 2.332 (1.04), 2.366 (0.89), 2.519(6.57), 2.524 (5.16), 2.665 (1.22), 2.670 (1.64), 2.675 (1.17), 2.710(1.02), 3.374 (9.15), 3.384 (16.00), 3.398 (9.35), 3.403 (8.04), 3.496(6.08), 3.511(8.53), 3.526 (9.23), 3.541 (10.37), 3.555 (9.13), 3.570(2.98), 4.368 (1.54), 4.389 (2.63), 4.410 (2.60), 4.431 (1.36), 4.695(3.97), 4.709 (8.81), 4.723 (3.84), 7.571 (5.28), 7.593 (10.15), 7.615(5.43), 7.623 (1.79), 8.163 (11.66), 8.186 (12.73), 8.500 (12.92), 8.522(11.44), 9.009 (15.93), 10.318 (6.25), 10.342 (5.98).

LC-MS (Method 3): R_(t)=1.87 min; MS (ESIpos): m/z=584 [M+H]⁺

Example 3657-[3-(2-Hydroxyethyl)-2-oxotetrahydropyrimidin-1(2H)-yl]-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 54 mg (78% purity, 91 μmol) of the compound fromExample 125A were reacted with 13.9 mg (109 μmol) of(2S)-1,1,1-trifluorobutan-2-amine in the presence of 41.6 mg (109 μmol)of HATU and 56 μl (0.32 mmol) of N,N-diisopropylethylamine in 1.5 ml ofdimethylformamide. The mixture was diluted with 1 ml of aqueous 1Nhydrochloric acid and 2 ml of DMSO and the solution was purified bymeans of preparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm,solvent: acetonitrile/0.1% formic acid gradient; 0 to 5 min 10%acetonitrile, over 14 min to 90% acetonitrile and for a further 2 min90% acetonitrile). 34.3 mg (65% of theory, 99% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: −0.008 (2.74), 0.008 (2.26), 0.961(7.23), 0.980 (16.00), 0.998 (7.82), 1.626 (1.06), 1.644 (1.46), 1.651(1.28), 1.661 (1.79), 1.670 (1.57), 1.679 (1.50), 1.687 (1.72), 1.705(1.28), 1.863 (1.46), 1.873 (2.05), 1.882 (2.48), 1.892 (5.19), 1.898(4.38), 1.908 (6.72), 1.917 (3.98), 1.923 (4.27), 1.938 (1.57), 3.369(5.52), 3.374 (7.82), 3.384 (13.41), 3.389 (11.76), 3.398 (7.96), 3.404(6.65), 3.497 (5.19), 3.512 (7.27), 3.527 (8.26), 3.541 (9.39), 3.555(8.26), 3.570 (2.59), 4.693 (4.02), 4.707 (9.13), 4.721 (4.24), 4.759(1.42), 4.778 (1.35), 7.566 (1.28), 7.574 (4.42), 7.596 (8.15), 7.618(4.46), 7.625 (1.39), 8.163 (9.86), 8.185 (10.85), 8.497 (10.85), 8.519(9.64), 9.017 (13.11), 10.174 (5.19), 10.198 (4.97).

LC-MS (Method 3): R_(t)=1.86 min; MS (ESIpos): m/z=572 [M+H]⁺

Example 366N-(Bicyclo[1.1.1]pent-1-yl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 50.0 mg (119 μmol) of the compound from Example 121Awere reacted with 17.0 mg (142 μmol) of bicyclo[1.1.1]pentan-1-aminehydrochloride in the presence of 54.1 mg (142 μmol) of HATU and 72 μl(0.42 mmol) of N,N-diisopropylethylamine in 1.5 ml of dimethylformamide.The mixture was diluted with 1 ml of aqueous 1N hydrochloric acid and 2ml of DMSO and the solution was purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.1%formic acid gradient; 0 to 5 min 10% acetonitrile, over 14 min to 90%acetonitrile and for a further 2 min 90% acetonitrile). 48.8 mg (84% oftheory, 99% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: −0.008 (1.55), 0.008 (1.50), 2.073(0.58), 2.093 (16.00), 2.476 (3.02), 5.136 (0.77), 5.218 (0.77), 6.738(1.36), 6.760 (1.37), 7.568 (0.82), 8.230 (1.64), 8.253 (1.57), 8.660(2.53), 10.283 (1.64).

LC-MS (Method 1): R_(t)=0.90 min; MS (ESIpos): m/z=487 [M+H]⁺

Example 367N-(3-Fluorobicyclo[1.1.1]pent-1-yl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 50.0 mg (119 μmol) of the compound from Example 117Awere reacted with 19.7 mg (143 μmol) of3-fluorobicyclo[1.1.1]pentan-1-amine hydrochloride in the presence of54.4 mg (143 μmol) of HATU and 73 μl (0.42 mmol) ofN,N-diisopropylethylamine in 1.5 ml of dimethylformamide. The mixturewas diluted with 1 ml of aqueous 1N hydrochloric acid and 2 ml of DMSOand the solution was purified by means of preparative HPLC (column:Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05% formicacid gradient; 0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrileand for a further 3 min 90% acetonitrile). 45.1 mg (68% of theory, 90%purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: −0.149 (0.64), −0.008 (5.57), 0.008(5.29), 2.073 (2.43), 2.113 (11.93), 2.328 (1.00), 2.332 (0.86), 2.349(4.57), 2.393 (5.29), 2.670 (1.07), 2.675 (0.79), 2.911 (4.64), 2.926(4.86), 2.954 (4.36), 2.969 (4.21), 3.339 (1.79), 3.454 (4.64), 3.484(5.64), 3.665 (4.14), 3.677 (5.14), 3.695 (4.00), 3.707 (3.50), 4.292(3.43), 5.324 (5.93), 5.332 (6.43), 7.595 (2.71), 7.601 (3.29), 7.614(4.93), 7.624 (5.00), 7.637 (3.29), 7.644 (2.64), 8.505 (1.43), 8.513(11.86), 8.527 (1.93), 8.535 (14.64), 8.665 (1.79), 8.672 (14.64), 8.687(1.50), 8.694 (11.43), 8.926 (1.64), 8.964 (16.00), 10.003 (1.14),10.119 (12.29).

LC-MS (Method 3): R_(t)=1.74 min; MS (ESIpos): m/z=503 [M+H]⁺

Example 3687-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-N-(3-fluorobicyclo[1.1.1]pent-1-yl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 50.0 mg (119 μmol) of the compound from Example 121Awere reacted with 19.6 mg (142 μmol) of3-fluorobicyclo[1.1.1]pentan-1-amine hydrochloride in the presence of54.1 mg (142 μmol) of HATU and 73 μl (0.420 mmol) ofN,N-diisopropylethylamine in 1.2 ml of dimethylformamide. The mixturewas diluted with 1 ml of aqueous 1N hydrochloric acid and 2 ml of DMSOand the solution was purified by means of preparative HPLC (column:Chromatorex C18, 10 m, 125×30 mm, solvent: acetonitrile/0.05% formicacid gradient; 0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrileand for a further 3 min 90% acetonitrile). 50.1 mg (75% of theory, 90%purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: −0.008 (3.60), 0.008 (3.27), 2.073(16.00), 2.094 (9.42), 2.476 (2.09), 3.047 (2.50), 3.079 (3.34), 3.222(2.02), 3.231 (2.25), 3.253 (1.66), 3.264 (1.66), 3.337 (3.32), 3.586(1.79), 3.595 (2.02), 3.612 (1.63), 3.623 (1.48), 3.922 (3.11), 4.044(3.06), 5.131 (4.39), 5.139 (4.31), 5.221 (4.39), 5.230 (4.21), 6.738(0.94), 6.747 (7.09), 6.760 (1.07), 6.770 (7.22), 7.546 (2.58), 7.562(4.49), 7.569 (4.52), 7.577 (1.68), 7.585 (2.65), 8.231 (1.48), 8.236(8.55), 8.253 (1.51), 8.258 (8.04), 8.660 (1.38), 8.700 (12.48), 10.283(0.92), 10.425 (9.08).

LC-MS (Method 3): R_(t)=1.57 min; MS (ESIpos): m/z=505 [M+H]⁺

Example 3697-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-4-oxo-N-[(2S)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 30 mg (71 μmol) of the compound from Example 121A werereacted with 13 mg (85 μmol) of(2S)-1,1,1-trifluoro-3,3-dimethylbutan-2-amine in the presence of 32 mg(85 μmol) of HATU and 43 μl (0.25 mmol) of N,N-diisopropylethylamine in1.0 ml of dimethylformamide. The mixture was diluted with 1 ml ofaqueous 1N hydrochloric acid and 2 ml of DMSO and the solution waspurified by means of preparative HPLC (column: Chromatorex C18, 10 μm,125×30 mm, solvent: acetonitrile/0.05% formic acid gradient; 0 to 3 min10% acetonitrile, to 35 min 90% acetonitrile and for a further 3 min 90%acetonitrile). 32.4 mg (81% of theory, 100% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: −0.008 (2.17), 0.008 (2.14), 1.089(16.00), 3.059 (0.72), 3.090 (0.96), 3.241 (0.66), 3.328 (1.22), 3.355(0.91), 3.610 (0.59), 3.929 (0.86), 4.052 (0.86), 4.621 (0.73), 5.138(1.04), 5.146 (1.08), 5.236 (1.02), 5.245 (1.02), 6.770 (2.04), 6.792(2.09), 7.548 (0.63), 7.560 (0.95), 7.570 (0.98), 7.583 (0.64), 8.295(2.41), 8.318 (2.25), 8.815 (3.51), 10.764 (1.24), 10.790 (1.18).

LC-MS (Method 3): R_(t)=1.88 min; MS (ESIpos): m/z=559 [M+H]⁺

Example 3707-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-4-oxo-N-(4,4,4-trifluoro-2-methylbutan-2-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 1.19 g (2.82 mmol) of the compound from Example 121Awere reacted with 601 mg (3.38 mmol) of4,4,4-trifluoro-2-methylbutan-2-amine hydrochloride in the presence of1.29 g (3.38 mmol) of HATU and 1.72 ml (9.87 mmol) ofN,N-diisopropylethylamine in 28 ml of dimethylformamide. The mixture wasadmixed with 40 ml of water and 15 ml of aqueous 1 M hydrochloric acidand extracted three times with 40 ml of ethyl acetate. The combinedorganic phases were washed with 30 ml of saturated aqueous sodiumchloride solution, dried and concentrated, and the residue was purifiedby means of normal phase chromatography (cyclohexane-ethyl acetategradient). Finally, the product was suspended in 10 ml of acetonitrileand additionally diluted with 15 ml of tert-butyl methyl ether. Themixture was extracted by stirring for 30 min and then filtered. Theprecipitate was filtered off with suction and dried under high vacuum.1.20 g (78% of theory, 100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]=10.17 (s, 1H), 8.69 (s, 1H), 8.26 (d,1H), 7.60-7.51 (m, 2H), 6.76 (d, 1H), 5.23 (d, 1H), 5.13 (d, 1H), 4.05(br. s, 1H), 3.93 (br. s, 1H), 3.61 (dd, 1H), 3.34 (s, 0.5H), 3.25 (dd,1H), 3.07 (d, 1H), 2.95 (q, 2H), 1.48 (s, 6H).

LC-MS (Method 3): R_(t)=1.71 min; MS (ESIpos): m/z=545 [M+H]⁺

Example 3717-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-4-oxo-N-[3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 30 mg (71 μmol) of the compound from Example 121A werereacted with 17 mg 8 μmol) of3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride in thepresence of 32.5 mg (85.4 μmol) of HATU and 43 μl (0.25 mmol) ofN,N-diisopropylethylamine in 1.0 ml of dimethylformamide. The mixturewas diluted with 1 ml of aqueous 1N hydrochloric acid and 2 ml of DMSOand the solution was purified by means of preparative HPLC (column:Chromatorex C18, 10 m, 125×30 mm, solvent: acetonitrile/0.05% formicacid gradient; 0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrileand for a further 3 min 90% acetonitrile). 27.6 mg (69% of theory, 99%purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: −0.008 (1.73), 0.008 (1.57), 2.073(7.45), 2.356 (16.00), 3.077 (0.74), 3.923 (0.74), 4.043 (0.74), 5.132(1.08), 5.141 (1.08), 5.222 (1.05), 5.232 (1.05), 6.749 (1.73), 6.771(1.75), 7.568 (1.12), 8.233 (2.13), 8.256 (2.00), 8.711 (3.43), 10.465(2.33).

LC-MS (Method 3): R_(t)=1.78 min; MS (ESIpos): m/z=555 [M+H]⁺

Example 3727-[(4S)-4-Hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 30 mg (71 μmol) of the compound from Example 117A werereacted with 17 mg (95% purity, 86 μmol) of3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride in thepresence of 33 mg (86 μmol) of HATU and 44 μl (0.25 mmol) ofN,N-diisopropylethylamine in 1.0 ml of dimethylformamide. The mixturewas diluted with 1 ml of aqueous 1N hydrochloric acid and 2 ml of DMSOand the solution was purified by means of preparative HPLC (column:Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05% formicacid gradient; 0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrileand for a further 3 min 90% acetonitrile). 24.3 mg (61% of theory, 99%purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: −0.008 (2.13), 0.008 (1.94), 2.349(0.88), 2.376 (16.00), 2.392 (1.16), 2.911 (0.75), 2.926 (0.78), 2.954(0.69), 2.969 (0.69), 3.454 (0.78), 3.484 (0.97), 3.666 (0.69), 3.677(0.85), 3.695 (0.66), 5.324 (1.66), 5.333 (1.66), 7.613 (0.81), 7.622(0.85), 8.514 (1.85), 8.536 (2.35), 8.671 (2.29), 8.693 (1.78), 8.974(2.79), 10.159 (2.32).

LC-MS (Method 3): R_(t)=1.95 min; MS (ESIpos): m/z=553 [M+H]⁺

Example 373 N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-(d1,1-dioxido-1,2,5-thiadiazolidin-2-yl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

104 mg (159 μmol) of the compound from example 127A were dissolved in 10ml of ethanol. 112 mg (20% purity, 159 μmol) palladium(II) hydroxide oncharcoal were added and hydrogenation was effected at standard pressureovernight. The reaction solution was filtered, and the filtrate wasconcentrated and purified by means of preparative HPLC (column:Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05% formicacid gradient; 0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrileand for a further 3 min 90% acetonitrile). A further purification waseffected by means of chiral preparative HPLC (column: Chiralpak IE 5 μm;flow rate: 15 ml/min; temp.: 35° C.; eluents: 25% ethanol, 75%n-heptane). 23.0 mg (25% of theory, 99% purity) of the title compoundwere obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: −0.149 (1.73), −0.008 (16.00), 0.008(12.76), 0.146 (1.66), 0.341 (2.75), 0.355 (2.60), 0.365 (1.62), 0.377(1.02), 0.538 (1.62), 0.548 (2.45), 0.562 (3.84), 0.579 (3.61), 0.598(1.92), 0.609 (1.58), 0.622 (0.98), 0.638 (1.17), 0.647 (1.47), 0.659(2.56), 0.668 (2.03), 0.680 (1.62), 0.693 (1.05), 1.186 (0.53), 1.198(1.05), 1.206 (1.43), 1.219 (2.48), 1.239 (2.79), 1.251 (1.51), 1.259(1.02), 2.327 (1.77), 2.366 (0.83), 2.523 (5.16), 2.665 (1.39), 2.670(1.88), 2.710 (0.87), 3.457 (3.46), 3.473 (8.24), 3.489 (4.40), 3.752(4.82), 3.767 (9.04), 3.783 (3.95), 4.368 (1.28), 4.389 (2.22), 4.409(2.18), 4.429 (1.20), 7.285 (7.98), 7.307 (8.06), 7.513 (4.44), 7.535(8.43), 7.557 (4.44), 8.037 (4.37), 8.651 (9.56), 8.673 (9.11), 9.002(13.55), 10.278 (5.12), 10.302 (4.93).

LC-MS (Method 3): R_(t)=1.95 min; MS (ESIpos): m/z=562 [M+H]⁺

Example 374N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-4-oxo-7-(2-oxo-1,3-oxazolidin-1.3-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 50.0 mg (105 μmol) of the compound from Example 126Awere reacted with 11.0 mg (126 μmol) of 1,3-oxazolidin-2-one in thepresence of 21.8 mg (158 μmol) of potassium carbonate, 2.4 mg (11 μmol)of palladium(II) acetate and 12 mg (21 μmol) of Xantphos in 0.75 ml of1,4-dioxane. Subsequently, the volume of the mixture was concentratedunder reduced pressure, and the residue was taken up with 1 ml ofaqueous 1N hydrochloric acid and 2 ml of acetonitrile and purified bymeans of preparative HPLC (column: Chromatorex C18, 10 m, 125×30 mm,solvent: acetonitrile/0.05% formic acid gradient; 0 to 3 min 10%acetonitrile, to 35 min 90% acetonitrile and for a further 3 min 90%acetonitrile). 33.6 mg (60% of theory, 99% purity) of the title compoundwere obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: −0.008 (1.85), 0.008 (1.34), 0.343(2.89), 0.357 (2.89), 0.369 (1.83), 0.380 (1.16), 0.541 (1.73), 0.551(2.65), 0.564 (4.20), 0.582 (4.03), 0.590 (2.61), 0.601 (2.20), 0.611(1.73), 0.624 (1.06), 0.641 (1.38), 0.650 (1.51), 0.661 (2.74), 0.671(2.24), 0.682 (1.85), 0.696 (1.19), 1.206 (1.14), 1.215 (1.60), 1.227(2.57), 1.235 (2.01), 1.248 (2.52), 1.260 (1.47), 1.268 (0.97), 2.073(1.68), 2.329 (0.69), 2.670 (0.82), 3.745 (4.87), 3.764 (8.60), 3.785(5.74), 4.372 (7.16), 4.393 (11.23), 4.412 (7.07), 4.437 (1.29), 7.563(5.18), 7.585 (9.68), 7.608 (5.18), 7.616 (1.64), 8.325 (9.92), 8.347(10.78), 8.719 (10.89), 8.741 (9.60), 9.063 (16.00), 10.243 (5.50),10.267 (5.30).

LC-MS (Method 3): R_(t)=2.10 min; MS (ESIpos): m/z=527 [M+H]⁺

Example 3757-[3-(2-Hydroxyethyl)-2-oxoimidazolidin-1-yl]-4-oxo-N-(4,4,4-trifluoro-2-methylbutan-2-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 30 mg (67 μmol) of the compound from Example 123A werereacted with 14 mg (80 μmol) of 4,4,4-trifluoro-2-methylbutan-2-aminehydrochloride in the presence of 38.2 mg (100 μmol) of HATU and 29.1 μl(170 μmol) of N,N-diisopropylethylamine in 2.0 ml of dimethylformamide.The mixture was diluted with 1 ml of 1N aqueous hydrochloric acid, 1 mlof acetonitrile and 1 ml of DMSO and the solution was purified by meansof preparative HPLC (column: Chromatorex C18, 10 m, 125×30 mm, solvent:acetonitrile/0.05% formic acid gradient; 0 to 3 min 10% acetonitrile, to35 min 90% acetonitrile and for a further 3 min 90% acetonitrile). 29.2mg (76% of theory, 100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: −0.008 (2.31), 0.008 (1.93), 1.495(16.00), 2.524 (1.37), 2.670 (0.45), 2.913 (0.72), 2.943 (2.05), 2.973(1.98), 3.003 (0.60), 3.255 (1.60), 3.270 (3.55), 3.284 (2.02), 3.488(1.52), 3.501 (3.04), 3.518 (4.32), 3.530 (3.12), 4.739 (1.17), 7.553(1.55), 7.574 (2.79), 7.596 (1.55), 8.410 (3.01), 8.433 (3.90), 8.542(4.00), 8.565 (2.88), 8.884 (4.99), 9.980 (3.23).

LC-MS (Method 3): R_(t)=1.89 min; MS (ESIpos): m/z=572 [M+H]⁺

Example 3764-Oxo-7-(2-oxoimidazolidin-11-yl)-N-(4,4,4-trifluoro-2-methylbutan-2-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 50.0 mg (124 μmol) of the compound from Example 113Awere reacted with 26.4 mg (148 μmol) of4,4,4-trifluoro-2-methylbutan-2-amine hydrochloride in the presence of56.4 mg (148 μmol) of HATU and 53.9 μl (309 μmol) ofN,N-diisopropylethylamine in 1.5 ml of dimethylformamide. The mixturewas diluted with 1 ml of 1N aqueous hydrochloric acid and 1 ml of DMSOand the solution was purified by means of preparative HPLC (column:Chromatorex C18, 10 m, 125×30 mm, solvent: acetonitrile/0.05% formicacid gradient; 0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrileand for a further 3 min 90% acetonitrile) and final normal phasechromatography (cyclohexane-ethyl acetate gradient). 35.7 mg (55% oftheory, 100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: −0.008 (1.14), 0.008 (1.01), 1.495(16.00), 2.524 (0.93), 2.913 (0.71), 2.943 (2.10), 2.973 (2.00), 3.003(0.62), 3.325 (1.57), 3.345 (2.21), 3.365 (1.69), 3.572 (1.77), 3.594(2.24), 3.612 (1.26), 7.550 (1.45), 7.572 (2.62), 7.594 (1.48), 7.649(2.43), 8.406 (2.75), 8.429 (3.80), 8.528 (3.71), 8.551 (2.69), 8.884(4.36), 9.985 (3.18).

LC-MS (Method 1): R_(t)=1.04 min; MS (ESIpos): m/z=528 [M+H]⁺

Example 377 Methyl{1-[5-oxo-6-{[(2S)-1,1,1-trifluorobutan-2-yl]carbamoyl}-8-(2,4,6-trifluorophenyl)-5,8-dihydro-1,8-naphthyridin-2-yl]imidazolidin-2-ylidene}carbamate

100 mg (205 μmol) of the compound from Example 128A and 57 μl (0.41mmol) of triethylamine were dissolved in 2.0 ml of dichloromethane. 32.0mg (205 μmol) of methyl (dichloromethylene)carbamate were added and themixture was stirred at RT overnight. The reaction mixture was admixedwith 20 ml of ethyl acetate and washed three times with saturatedaqueous sodium hydrogencarbonate solution. The organic phase was washedwith saturated aqueous sodium chloride solution, dried and concentrated.The residue was purified by means of preparative HPLC (column:Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.1% formicacid gradient; 0 to 5 min 10% acetonitrile, over 14 min to 90%acetonitrile and for a further 2 min 90% acetonitrile). 33.7 mg (29% oftheory, 100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.008 (1.62), 0.963 (2.65), 0.981(5.90), 1.000 (2.87), 1.645 (0.55), 1.662 (0.64), 1.670 (0.54), 1.686(0.62), 1.705 (0.42), 1.865 (0.50), 1.874 (0.56), 1.883 (0.54), 1.893(0.64), 1.909 (0.50), 1.928 (0.42), 2.329 (0.42), 2.670 (0.48), 3.520(0.91), 3.541 (2.07), 3.563 (1.92), 3.611 (16.00), 3.655 (2.02), 3.678(2.20), 3.697 (0.96), 4.757 (0.55), 7.565 (1.66), 7.587 (3.13), 7.609(1.67), 8.623 (3.35), 8.646 (3.76), 8.918 (4.03), 8.940 (3.39), 8.964(1.06), 9.027 (5.59), 10.171 (1.83), 10.194 (1.78).

LC-MS (Method 1): R_(t)=1.07 min; MS (ESIpos): m/z=571 [M+H]⁺

Example 378N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-{[(2R)-2-hydroxypropyl]amino}-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP3, 150 mg (315 μmol) of the compound from Example 126Awere reacted with 33.2 mg (441 μmol) of (2R)-1-aminopropan-2-ol in thepresence of 190 μl (1.10 mmol) of N,N-diisopropylethylamine in 3.1 ml ofdimethylformamide. The reaction mixture was diluted with 1 ml ofacetonitrile and 0.5 ml of water and purified by means of preparativeHPLC (column: Chromatorex C18, 10 μm, 125×30 mm, solvent:acetonitrile/0.1% formic acid gradient; 0 to 5 min 10% acetonitrile,over 14 min to 90% acetonitrile and for a further 2 min 90%acetonitrile). 145 mg (89% of theory, 99% purity) of the title compoundwere obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: −0.150 (0.47), −0.008 (4.10), 0.008(3.55), 0.146 (0.47), 0.307 (1.05), 0.318 (2.37), 0.329 (3.71), 0.341(3.77), 0.353 (2.84), 0.365 (1.52), 0.490 (0.99), 0.501 (2.60), 0.513(3.85), 0.525 (3.29), 0.535 (2.80), 0.542 (2.68), 0.549 (2.43), 0.562(3.79), 0.573 (3.22), 0.583 (2.96), 0.593 (2.41), 0.607 (1.52), 0.622(1.82), 0.632 (2.17), 0.643 (3.31), 0.653 (3.10), 0.658 (3.00), 0.667(3.08), 0.675 (1.42), 0.688 (1.03), 0.826 (15.80), 0.842 (16.00), 1.159(0.79), 1.171 (1.54), 1.179 (2.27), 1.191 (3.91), 1.200 (2.72), 1.212(3.87), 1.224 (1.99), 1.232 (1.34), 1.244 (0.59), 2.073 (14.17), 2.328(1.01), 2.333 (0.75), 2.366 (0.79), 2.519 (4.28), 2.524 (3.26), 2.666(0.79), 2.670 (1.01), 2.710 (0.81), 2.762 (1.12), 2.778 (1.74), 2.795(2.58), 2.813 (2.31), 2.828 (1.48), 2.984 (1.68), 2.997 (2.51), 3.009(2.11), 3.029 (1.91), 3.042 (1.40), 3.559 (2.55), 4.330 (0.51), 4.350(1.93), 4.370 (3.26), 4.392 (3.26), 4.412 (1.74), 4.639 (5.68), 4.650(5.74), 6.729 (6.67), 6.752 (6.89), 7.535 (6.41), 7.556 (11.17), 7.578(6.29), 8.137 (6.29), 8.160 (8.19), 8.174 (4.42), 8.188 (2.37), 8.765(13.93), 10.591 (5.58), 10.615 (5.31).

LC-MS (Method 1): R_(t)=1.00 min; MS (ESIpos): m/z=515 [M+H]⁺

Example 379N-(2-Cyclopropylpropan-2-yl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 30 mg (71 μmol) of the compound from Example 121A werereacted with 8.5 mg (85 μmol) of 2-cyclopropylpropan-2-amine in thepresence of 32 mg (85 μmol) of HATU and 43 μl (0.25 μmol) ofN,N-diisopropylethylamine in 1.0 ml of dimethylformamide. The mixturewas diluted with 1 ml of water and 2 ml of DMSO and the solution waspurified by means of preparative HPLC (column: Chromatorex C18, 10 m,125×30 mm, solvent: acetonitrile/0.1% formic acid gradient; 0 to 5 min10% acetonitrile, over 14 min to 90% acetonitrile and for a further 2min 90% acetonitrile). 21.9 mg (61% of theory, 100% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.396 (5.13), 0.414 (4.63), 1.311(16.00), 2.073 (2.35), 3.049 (0.58), 3.080 (0.80), 3.230 (0.49), 3.253(0.41), 3.336 (0.74), 3.594 (0.49), 3.921 (0.75), 4.042 (0.75), 5.129(0.82), 5.221 (0.81), 6.728 (1.58), 6.751 (1.58), 7.536 (0.69), 7.555(1.16), 7.578 (0.64), 8.256 (1.85), 8.278 (1.73), 8.642 (3.25), 9.938(2.06).

LC-MS (Method 1): R_(t)=0.89 min; MS (ESIpos): m/z=503 [M+H]⁺

Example 3807-(3-Cyano-2-oxotetrahydropyrimidin-1(2H)-yl)-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 100 mg (210 μmol) of the compound from Example 126Awere reacted with 28.9 mg (231 μmol) of2-oxotetrahydropyrimidin-1(2H)-carbonitrile in the presence of 43.6 mg(315 μmol) of potassium carbonate, 4.7 mg (21 μmol) of palladium(II)acetate and 24 mg (42 μmol) of Xantphos in 2.1 ml of 1,4-dioxane.Subsequently, 2 ml of water and 3 ml of acetonitrile were added.Purification was effected by means of preparative HPLC (column:Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.1% formicacid gradient; 0 to 5 min 10% acetonitrile, over 14 min to 90%acetonitrile and for a further 2 min 90% acetonitrile). 74.0 mg (62% oftheory, 100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: −0.149 (1.15), −0.008 (8.97), 0.008(8.97), 0.146 (1.12), 0.343 (2.62), 0.356 (2.87), 0.558 (2.55), 0.571(4.38), 0.584 (3.80), 0.652 (1.63), 0.674 (2.59), 1.232 (2.68), 1.252(2.40), 2.026 (3.86), 2.040 (5.17), 2.055 (4.09), 2.073 (11.15), 2.328(1.92), 2.367 (0.93), 2.671 (1.88), 2.710 (0.89), 3.589 (5.05), 3.603(6.71), 3.617 (5.01), 3.812 (5.43), 3.827 (9.52), 3.841 (5.37), 4.367(1.31), 4.389 (2.49), 4.409 (2.14), 7.579 (4.89), 7.601 (9.10), 7.624(5.05), 8.136 (11.08), 8.158 (11.31), 8.695 (11.98), 8.717 (10.57),9.089 (16.00), 10.195 (5.37), 10.219 (4.89).

LC-MS (Method 1): R_(t)=1.08 min; MS (ESIpos): m/z=565 [M+H]⁺

Example 3817-[(4R)-4-Methyl-2-oxoimidazolidin-1-yl]-4-oxo-N-[(2S)-1-(trifluoromethoxy)propan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 100 mg (97% purity, 232 μmol) of the compound fromExample 129D were reacted with 50.0 mg (278 μmol) of(2S)-1-(trifluoromethoxy)propan-2-amine hydrochloride in the presence of106 mg (278 μmol) of HATU and 101 μl (580 μmol) ofN,N-diisopropylethylamine in 2.3 ml of dimethylformamide. The mixturewas diluted with 1 ml of 1N aqueous hydrochloric acid, water andacetonitrile and the solution was purified by means of preparative HPLC(column: Chromatorex C18, 10 m, 125×30 mm, solvent: acetonitrile/0.1%formic acid gradient; 0 to 5 min 10% acetonitrile, over 14 min to 90%acetonitrile and for a further 2 min 90% acetonitrile). 69.3 mg (55% oftheory, 100% purity) of the title compound were obtained.

¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: −0.007 (0.71), 0.007 (0.68), 1.120(10.98), 1.131 (11.18), 1.233 (0.41), 1.256 (16.00), 1.270 (15.96),2.516 (2.00), 2.520 (1.59), 2.524 (1.18), 3.084 (1.25), 3.093 (2.58),3.104 (2.65), 3.112 (1.27), 3.711 (1.38), 3.728 (3.72), 3.745 (3.68),3.749 (3.29), 3.763 (1.38), 3.780 (0.61), 4.157 (0.78), 4.166 (1.11),4.177 (4.39), 4.184 (5.76), 4.193 (4.96), 4.203 (0.92), 4.213 (1.01),4.335 (0.64), 4.345 (1.15), 4.359 (1.55), 4.373 (1.09), 4.383 (0.52),7.550 (1.03), 7.554 (1.02), 7.569 (4.16), 7.587 (4.18), 7.607 (1.02),7.808 (5.93), 8.406 (8.66), 8.424 (10.07), 8.538 (10.69), 8.556 (8.06),8.904 (12.01), 9.902 (3.85), 9.917 (3.70).

LC-MS (Method 3): R_(t)=1.91 min; MS (ESIpos): m/z=544 [M+H]⁺

Example 382N-(1,1-Difluoro-2-methylpropan-2-yl)-7-[3-(2-hydroxyethyl)-2-oxotetrahydropyrimidin-1(2H)-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 25 mg (97% purity, 52 μmol) of the compound fromExample 125A were reacted with 9.2 mg (63 μmol) of1,1-difluoro-2-methylpropan-2-amine hydrochloride in the presence of 24mg (63 μmol) of HATU and 23 μl (0.13 mmol) of N,N-diisopropylethylaminein 1.4 ml of dimethylformamide. The mixture was diluted with 1 ml of 1Naqueous hydrochloric acid, water and acetonitrile and the solution waspurified by means of preparative HPLC (column: Chromatorex C18, 10 μm,125×30 mm, solvent: acetonitrile/0.1% formic acid gradient; 0 to 5 min10% acetonitrile, over 14 min to 90% acetonitrile and for a further 2min 90% acetonitrile). 16.2 mg (56% of theory, 100% purity) of the titlecompound were obtained.

¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: −0.007 (0.86), 0.006 (0.84), 1.451(16.00), 1.880 (0.39), 1.891 (1.10), 1.904 (1.70), 1.916 (1.18), 1.927(0.41), 2.515 (2.23), 2.518 (1.70), 2.522 (1.29), 3.368 (1.68), 3.373(2.29), 3.380 (4.11), 3.385 (3.51), 3.392 (2.47), 3.397 (2.00), 3.494(1.65), 3.506 (2.23), 3.518 (1.63), 3.528 (1.16), 3.539 (2.88), 3.551(2.60), 3.563 (0.84), 4.688 (1.27), 4.699 (2.94), 4.710 (1.25), 6.317(0.84), 6.431 (1.63), 6.544 (0.76), 7.571 (1.39), 7.588 (2.45), 7.606(1.37), 8.140 (3.64), 8.158 (3.68), 8.484 (3.92), 8.502 (3.43), 8.927(5.03), 10.099 (3.13).

LC-MS (Method 3): R_(t)=1.80 min; MS (ESIpos): m/z=554 [M+H]⁺

Example 3837-[3-(2-Hydroxyethyl)-2-oxotetrahydropyrimidin-1(2H)-yl]-4-oxo-N-(4,4,4-trifluoro-2-methylbutan-2-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 19 mg (99% purity, 41 μmol) of the compound fromExample 125A were reacted with 8.7 mg (49 μmol) of4,4,4-trifluoro-2-methylbutan-2-amine hydrochloride in the presence of19 mg (49 μmol) of HATU and 18 μl (0.10 mmol) ofN,N-diisopropylethylamine in 1.0 ml of dimethylformamide. The mixturewas diluted with 1 ml of aqueous 1N hydrochloric acid, water andacetonitrile and the solution was purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.1%formic acid gradient; 0 to 5 min 10% acetonitrile, over 14 min to 90%acetonitrile and for a further 4 min 90% acetonitrile). 9.30 mg (39% oftheory, 100% purity) of the title compound were obtained.

¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.497 (16.00), 1.880 (0.42), 1.892(1.17), 1.904 (1.81), 1.916 (1.24), 1.928 (0.45), 2.519 (0.74), 2.523(0.56), 2.924 (0.69), 2.948 (2.01), 2.972 (1.89), 2.996 (0.57), 3.369(1.76), 3.374 (2.47), 3.381 (4.30), 3.386 (3.67), 3.392 (2.62), 3.398(2.12), 3.495 (1.74), 3.507 (2.38), 3.519 (1.71), 3.529 (1.21), 3.541(2.97), 3.552 (2.69), 3.564 (0.87), 4.689 (1.27), 4.700 (2.92), 4.711(1.25), 7.569 (1.48), 7.587 (2.61), 7.604 (1.47), 8.136 (3.98), 8.154(3.98), 8.478 (4.27), 8.496 (3.72), 8.904 (5.42), 9.962 (3.28).

LC-MS (Method 3): R_(t)=1.88 min; MS (ESIpos): m/z=586 [M+H]⁺

Example 384N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[(2-hydroxyethyl)(methyl)amino]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP3, 50.0 mg (105 μmol) of the compound from Example 126Awere reacted with 8.7 mg (116 μmol) of 2-(methylamino)ethanol in thepresence of 64 μl (0.37 mmol) of N,N-diisopropylethylamine in 0.56 ml ofdimethylformamide. The reaction mixture was diluted with 1 ml ofacetonitrile and 0.2 ml of 1N aqueous hydrochloric acid and purified bymeans of preparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm,solvent: acetonitrile/0.05% formic acid gradient; 0 to 3 min 10%acetonitrile, to 35 min 90% acetonitrile and for a further 3 min 90%acetonitrile). 43.6 mg (81% of theory, 100% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.313 (1.08), 0.324 (2.62), 0.334(4.16), 0.346 (4.12), 0.358 (3.20), 0.370 (1.57), 0.498 (1.08), 0.510(2.93), 0.521 (4.27), 0.534 (3.75), 0.547 (3.80), 0.556 (3.35), 0.567(4.19), 0.578 (3.62), 0.588 (3.27), 0.599 (2.68), 0.612 (1.63), 0.626(2.04), 0.636 (2.30), 0.647 (3.74), 0.658 (3.39), 0.663 (3.25), 0.671(3.20), 0.679 (1.57), 0.692 (1.03), 1.164 (0.78), 1.176 (1.59), 1.184(2.37), 1.196 (4.08), 1.205 (3.00), 1.217 (3.98), 1.229 (2.16), 1.237(1.46), 1.249 (0.63), 2.328 (0.79), 2.366 (0.64), 2.670 (0.91), 2.711(0.79), 2.833 (1.26), 3.123 (2.01), 3.538 (1.66), 4.332 (0.55), 4.352(2.17), 4.373 (3.82), 4.394 (3.72), 4.414 (1.97), 4.434 (0.48), 4.615(0.72), 6.961 (1.39), 7.525 (5.57), 7.547 (10.59), 7.569 (5.53), 8.261(2.60), 8.280 (2.50), 8.805 (16.00), 10.546 (6.57), 10.570 (6.32).

LC-MS (Method 3): R_(t)=1.93 min; MS (ESIpos): m/z=515 [M+H]⁺

Example 385N-[6-{[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]carbamoyl}-5-oxo-8-(2,4,6-trifluorophenyl)-5,8-dihydro-1,8-naphthyridin-2-yl]-N-methylglycine

According to GP3, 50.0 mg (105 μmol) of the compound from Example 126Awere reacted with 50.0 mg (325 μmol) of ethyl N-methylglycinatehydrochloride in the presence of 64 μl (0.37 mmol) ofN,N-diisopropylethylamine in 1.0 ml of dimethylformamide. The reactionmixture was diluted with 1 ml of acetonitrile and 0.2 ml of aqueous 1Nhydrochloric acid and purified by means of preparative HPLC (column:Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.1% formicacid gradient; 0 to 5 min 10% acetonitrile, over 14 min to 90%acetonitrile and for a further 4 min 90% acetonitrile). 32.0 mg (56% oftheory, 96% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]=12.44 (br. s, 1H), 10.50 (d, 1H), 8.81(s, 1H), 8.41-8.25 (m, 1H), 7.62-7.35 (m, 2H), 7.08-6.87 (m, 1H),4.44-4.32 (m, 1H), 3.95 (br. s, 1.4H), 3.15 (br. s, 2.3H), 2.81 (br. s,0.5H), 1.26-1.16 (m, 1H), 0.70-0.49 (m, 3H), 0.38-0.30 (m, 1H).

LC-MS (Method 3): R_(t)=1.85 min; MS (ESIpos): m/z=529 [M+H]⁺

Example 386N-[(1R)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 11.0 g (26.2 mmol) of the compound from Example 117Awere reacted with 5.53 g (31.5 mmol) of(1R)-1-cyclopropyl-2,2,2-trifluoroethanamine hydrochloride in thepresence of 15.0 g (39.3 mmol) of HATU and 11.4 ml (65.6 mmol) ofN,N-diisopropylethylamine in 150 ml of dimethylformamide. The mixturewas stirred at room temperature for a further 1.5 h and then the mixturewas extracted by stirring in ice-water with a little aqueoushydrochloric acid. The precipitate was filtered off with suction andwashed with water. The residue was purified by means of normal phasechromatography (petroleum ether/ethyl acetate 1:1 anddichloromethane/methanol 9:1). 11 g (76% of theory, 99% purity) of thetitle compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: −0.008 (2.46), 0.008 (2.09), 0.332(1.29), 0.337 (1.43), 0.346 (2.78), 0.358 (2.64), 0.371 (1.67), 0.381(1.15), 0.541 (1.63), 0.551 (2.52), 0.565 (3.70), 0.582 (3.68), 0.591(2.39), 0.602 (1.99), 0.612 (1.61), 0.626 (1.01), 0.640 (1.25), 0.649(1.45), 0.661 (2.70), 0.670 (2.11), 0.685 (1.57), 0.696 (1.07), 1.106(1.49), 1.175 (1.11), 1.193 (1.07), 1.206 (1.09), 1.214 (1.51), 1.227(2.50), 1.235 (1.85), 1.247 (2.48), 1.259 (1.37), 1.268 (0.95), 1.989(2.03), 2.356 (3.72), 2.399 (4.35), 2.731 (0.83), 2.891 (1.09), 2.917(3.56), 2.931 (3.74), 2.960 (3.30), 2.974 (3.20), 3.463 (3.74), 3.493(4.55), 3.674 (3.26), 3.685 (4.03), 3.703 (3.10), 3.715 (2.74), 4.290(2.76), 4.299 (2.78), 4.378 (1.33), 4.398 (2.29), 4.420 (2.21), 4.440(1.21), 5.330 (9.02), 5.339 (8.94), 7.592 (2.15), 7.600 (2.80), 7.611(4.09), 7.622 (4.09), 7.635 (2.74), 7.642 (2.07), 8.533 (10.41), 8.556(12.48), 8.710 (12.66), 8.733 (9.92), 9.064 (16.00), 10.249 (5.43),10.273 (5.21).

LC-MS (Method 3): R_(t)=1.87 min; MS (ESIpos): m/z=541 [M+H]⁺

Example 387N-[(1R)-1-Cyclopropyl-2,2,2-trifluoroethyl]-1-(2,6-dichloro-4-fluorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 150 mg (99% purity, 292 μmol) of the compound fromExample 130C were reacted with 32.5 mg (321 μmol) of(4S)-4-hydroxypyrrolidin-2-one in the presence of 60.5 mg (438 μmol) ofpotassium carbonate, 6.6 mg (29 μmol) of palladium(II) acetate and 34 mg(58 μmol) of Xantphos in 3.0 ml of 1,4-dioxane. Subsequently, thereaction mixture was diluted with acetonitrile and filtered, and thesolvent was removed under reduced pressure. The residue was taken up in3 ml of acetonitrile and 0.5 ml of water and purified by means ofpreparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm, solvent:acetonitrile/0.05% formic acid gradient; 0 to 3 min. 10% acetonitrile to22 min. 55% acetonitrile, to 35 min. 65% ACN and a further 3 min. 90%acetonitrile), and 25 mg (15% of theory, 97.6% purity) of the titlecompound were obtained. Subsequently, the mixed fractions were purifiedagain by means of normal phase chromatography (dichloromethane-methanolgradient), and a further 89.2 mg (52% of theory, 97% purity) of thetitle compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: −0.008 (3.21), 0.008 (3.00), 0.343(0.98), 0.353 (1.81), 0.365 (1.66), 0.554 (1.65), 0.569 (2.02), 0.587(2.18), 0.597 (1.50), 0.607 (1.29), 0.645 (0.88), 0.655 (0.93), 0.666(1.86), 0.676 (1.40), 1.214 (0.99), 1.227 (1.61), 1.235 (1.22), 1.248(1.52), 1.259 (0.91), 2.073 (1.27), 2.341 (2.38), 2.386 (2.72), 2.912(2.30), 2.927 (2.35), 2.956 (2.17), 2.970 (2.05), 3.287 (2.77), 3.375(2.46), 3.404 (3.01), 3.597 (2.13), 3.610 (2.53), 3.627 (2.05), 3.640(1.73), 4.270 (1.84), 4.385 (1.48), 4.406 (1.43), 5.329 (5.75), 5.338(5.59), 7.906 (1.99), 7.913 (5.03), 7.923 (4.69), 7.929 (3.13), 7.934(4.95), 7.943 (4.50), 7.950 (2.09), 8.531 (7.38), 8.553 (8.44), 8.723(8.78), 8.746 (6.86), 9.004 (16.00), 10.285 (3.50), 10.309 (3.47).

LC-MS (Method 3): R_(t)=2.01 min; MS (ESIpos): m/z=573 [M+H]⁺

Example 3881-(2,6-Dichloro-4-fluorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 150 mg (99% purity, 299 μmol) of the compound fromExample 131A were reacted with 33.3 mg (329 μmol) of(4S)-4-hydroxypyrrolidin-2-one in the presence of 62.0 mg (448 μmol) ofpotassium carbonate, 6.7 mg (30 μmol) of palladium(II) acetate and 35 mg(60 μmol) of Xantphos in 3.3 ml of 1,4-dioxane. Subsequently, thereaction mixture was diluted with acetonitrile and filtered, and thesolvent was removed under reduced pressure. The residue was taken up in3.0 ml of acetonitrile and 0.5 ml of water and separated by means ofpreparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm, solvent:acetonitrile/0.05% formic acid gradient; 0 to 3 min. 10% acetonitrile to22 min. 55% acetonitrile, to 35 min. 65% ACN and a further 3 min. 90%acetonitrile). The product-containing fractions were combined andpurified again by means of normal phase chromatography(dichloromethane-methanol gradient). 65.2 mg (39% of theory, 100%purity) of the title compound were obtained.

¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: −0.007 (5.14), 0.007 (4.29), 0.971(5.91), 0.986 (12.43), 1.001 (6.04), 1.648 (0.89), 1.662 (1.16), 1.667(1.00), 1.676 (1.35), 1.682 (1.22), 1.690 (1.13), 1.696 (1.26), 1.710(0.96), 1.875 (0.98), 1.883 (1.18), 1.890 (1.18), 1.898 (1.35), 1.903(1.18), 1.911 (1.05), 1.918 (0.89), 2.347 (2.86), 2.381 (3.23), 2.919(2.46), 2.931 (2.64), 2.954 (2.35), 2.965 (2.27), 3.286 (5.71), 3.376(2.94), 3.400 (3.42), 3.603 (2.38), 3.613 (2.88), 3.627 (2.33), 3.637(2.05), 4.259 (0.98), 4.269 (2.16), 4.278 (2.07), 4.767 (1.09), 4.783(1.02), 5.328 (6.02), 5.336 (6.02), 5.754 (16.00), 7.912 (2.07), 7.917(4.66), 7.927 (5.43), 7.934 (5.84), 7.944 (4.19), 7.949 (2.27), 8.531(7.28), 8.549 (8.15), 8.721 (8.61), 8.739 (6.95), 9.010 (15.72), 10.140(3.84), 10.159 (3.71).

LC-MS (Method 3): R_(t)=1.97 min; MS (ESIpos): m/z=561 [M+H]⁺

Example 3891-(2,6-Dichloro-4-fluorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 150 mg (99% purity, 299 μmol) of the compound fromExample 132A were reacted with 33.3 mg (329 μmol) of(4S)-4-hydroxypyrrolidin-2-one in the presence of 62.0 mg (448 μmol) ofpotassium carbonate, 6.7 mg (30 μmol) of palladium(II) acetate and 35 mg(60 μmol) of Xantphos in 3.0 ml of 1,4-dioxane. Subsequently, thereaction mixture was diluted with acetonitrile and filtered, and thesolvent was removed under reduced pressure. The residue was taken up in3.0 ml of acetonitrile and 0.5 ml of water and separated by means ofpreparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm, solvent:acetonitrile/0.05% formic acid gradient; 0 to 3 min. 10% acetonitrile to22 min. 55% acetonitrile, to 35 min. 65% ACN and a further 3 min. 90%acetonitrile). The product-containing fractions were combined andpurified again by means of normal phase chromatography(dichloromethane-methanol gradient). 13.0 mg (8% of theory, 99% purity)of the title compound were obtained.

¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: −0.120 (1.67), −0.013 (2.76), −0.007(16.00), 0.007 (13.28), 0.117 (1.63), 0.971 (3.73), 0.986 (7.69), 1.001(3.73), 1.147 (1.17), 1.236 (1.36), 1.662 (0.74), 1.667 (0.66), 1.675(0.89), 1.682 (0.82), 1.690 (0.78), 1.695 (0.82), 1.710 (0.58), 1.875(0.62), 1.882 (0.74), 1.890 (0.78), 1.898 (0.85), 1.911 (0.66), 1.917(0.58), 2.347 (1.75), 2.358 (0.85), 2.362 (1.05), 2.365 (0.82), 2.381(1.98), 2.632 (0.74), 2.635 (1.05), 2.639 (0.74), 2.919 (1.55), 2.931(1.63), 2.953 (1.48), 2.965 (1.40), 3.285 (10.17), 3.376 (1.90), 3.399(2.10), 3.603 (1.51), 3.613 (1.79), 3.627 (1.44), 3.637 (1.24), 4.277(1.32), 4.767 (0.70), 5.328 (3.77), 5.335 (3.69), 5.754 (4.97), 7.912(1.32), 7.917 (2.95), 7.927 (3.42), 7.934 (3.65), 7.944 (2.64), 7.949(1.44), 8.531 (4.58), 8.548 (5.13), 8.721 (5.40), 8.739 (4.35), 9.010(10.02), 10.140 (2.37), 10.159 (2.29).

LC-MS (Method 3): R_(t)=1.98 min; MS (ESIpos): m/z=561 [M+H]⁺

Example 3901-(2-Chloro-4,6-difluorophenyl)-7-[(2R,4S)-4-hydroxy-2,4-dimethylpyrrolidin-1-yl]-4-oxo-N-[(2S)-1,1,1-trifluoropropan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP3, 18 mg (38 μmol) of the compound from Example 111A werereacted with 10 mg (95% purity, 41 μmol) of the compound from Example116A in the presence of 23 μl (0.13 mmol) of N,N-diisopropylethylaminein 1.5 ml of dimethylformamide. The reaction mixture was diluted with 4ml of acetonitrile and 0.5 ml of water and purified by means ofpreparative HPLC (column: Kromasil C18, 10 μm, 250×20 mm, solvent:acetonitrile/0.05% formic acid gradient; 0 to 3 min 10% acetonitrile, to35 min 90% acetonitrile and for a further 3 min 90% acetonitrile). 15.9mg (77% of theory, 99% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: −0.149 (0.98), −0.008 (15.59), 0.008(9.15), 0.146 (0.94), 0.976 (4.35), 1.021 (3.73), 1.267 (12.23), 1.365(14.65), 1.371 (16.00), 1.382 (14.36), 1.388 (14.61), 1.648 (2.13),2.001 (1.76), 2.328 (0.90), 2.367 (0.98), 2.711 (1.11), 3.288 (13.09),3.465 (2.26), 3.752 (1.76), 4.865 (5.87), 4.898 (2.91), 6.702 (2.38),7.710 (4.76), 7.733 (5.46), 7.749 (3.24), 8.246 (5.91), 8.268 (5.46),8.761 (5.70), 10.493 (7.30), 10.516 (7.06).

LC-MS (Method 3): R_(t)=2.07 min; MS (ESIpos): m/z=545 [M+H]⁺

Example 3911-(2-Chloro-4,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-N-(4,4,4-trifluoro-2-methylbutan-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Atropisomer Mixture)

According to GP3, 100 mg (202 μmol) of the compound from Example 109Awere reacted with 33.9 mg (243 μmol) of (3R,4R)-pyrrolidine-3,4-diolhydrochloride in the presence of 123 μl (708 μmol) ofN,N-diisopropylethylamine in 2.0 ml of dimethylformamide. The reactionmixture was diluted with 2.0 ml of acetonitrile and acidified with 1Naqueous hydrochloric acid. The solution was purified by means ofpreparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm, solvent:acetonitrile/0.1% formic acid gradient; 0 to 5 min 10% acetonitrile,over 14 min to 90% acetonitrile and for a further 4 min 90%acetonitrile). 109 mg (96% of theory, 100% purity) of the title compoundwere obtained.

LC-MS (Method 3): R_(t)=1.76 min; MS (ESIpos): m/z=561 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]=10.19 (s, 1H), 8.63 (s, 1H), 8.26 (d,1H), 7.76-7.65 (m, 2H), 6.75 (d, 1H), 5.24-5.19 (m, 1H), 5.15-5.10 (m,1H), 4.04 (br. s, 1H), 3.91 (br. s, 1H), 3.64-3.56 (m, 1H), 3.24-3.15(m, 1H), 3.06-2.87 (m, 3H), 1.48 (s, 6H).

109 mg of the title compound (atropisomer mixture) were separated intothe atropisomers by chiral SFC (preparative SFC: column: DaicelChiralpak IE 5 μm 250×20 mm; eluent: 80% isoheptane, 20% ethanol;temperature: 35° C.; flow rate: 15 ml/min; UV detection: 220 nm).

This gave (in the sequence of elution from the column) 45.1 mg ofatropisomer 1 from Example 392 (99% de) Rt=5.56 min and 47.9 mg (99% de)of atropisomer 2 from Example 393 R_(t)=6.17 min.

[Analytical SFC: column: Daicel Chiralpak IE 5 μm 250×4.6 mm; eluent:75% isohexane, 25% ethanol; temperature: 50° C.; flow rate: 1 ml/min; UVdetection: 220 nm]

Example 3921-(2-Chloro-4,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-N-(4,4,4-trifluoro-2-methylbutan-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Atropisomer 1)

LC-MS (Method 3): R_(t)=1.75 min; MS (ESIpos): m/z=561 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]=10.19 (s, 1H), 8.63 (s, 1H), 8.26 (d,1H), 7.76-7.65 (m, 2H), 6.75 (d, 1H), 5.24-5.19 (m, 1H), 5.15-5.11 (m,1H), 4.04 (br. s, 1H), 3.91 (br. s, 1H), 3.64-3.56 (m, 1H), 3.23-3.15(m, 1H), 3.06-2.87 (m, 3H), 1.48 (s, 6H).

Example 3931-(2-Chloro-4,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-N-(4,4,4-trifluoro-2-methylbutan-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Atropisomer 2)

LC-MS (Method 3): R_(t)=1.75 min; MS (ESIpos): m/z=561 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]=10.19 (s, 1H), 8.63 (s, 1H), 8.26 (d,1H), 7.76-7.66 (m, 2H), 6.75 (d, 1H), 5.25-5.19 (m, 1H), 5.15-5.11 (m,1H), 4.04 (br. s, 1H), 3.91 (br. s, 1H), 3.64-3.56 (m, 1H), 3.25-3.17(m, 1H), 3.04-2.88 (m, 3H), 1.48 (s, 6H).

Example 3941-(2-Chloro-4,6-difluorophenyl)-4-oxo-7-(2-oxoimidazolidin-1-yl)-N-(4,4,4-trifluoro-2-methylbutan-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 30 mg (61 μmol) of the compound from Example 109A werereacted with 54.4 mg (96% purity, 607 μmol) of imidazolidin-2-one in thepresence of 13 mg (91 μmol) of potassium carbonate, 1.4 mg (6.1 μmol) ofpalladium(II) acetate and 7.0 mg (12 μmol) of Xantphos in 0.6 ml of1,4-dioxane. This was followed by dilution with 3.0 ml of acetonitrileand 2.0 ml of water. Purification was effected by means of preparativeHPLC (column: Chromatorex C18, 10 μm, 125×30 mm, solvent:acetonitrile/0.1% formic acid gradient; 0 to 5 min 10% acetonitrile,over 14 min to 90% acetonitrile and for a further 4 min 90%acetonitrile). 15.6 mg (45% of theory, 96% purity) of the title compoundwere obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: −0.149 (0.53), −0.008 (6.12), 0.008(4.31), 0.146 (0.52), 1.234 (0.65), 1.259 (0.46), 1.496 (16.00), 2.073(0.62), 2.323 (0.42), 2.328 (0.55), 2.523 (2.22), 2.665 (0.48), 2.670(0.59), 2.906 (0.49), 2.918 (0.49), 2.937 (1.31), 2.948 (1.32), 2.966(1.25), 2.978 (1.28), 2.997 (0.42), 3.008 (0.42), 3.335 (3.40), 3.354(2.11), 3.516 (1.27), 3.526 (1.37), 3.535 (2.07), 3.546 (1.59), 3.567(0.89), 7.641 (2.91), 7.685 (0.64), 7.691 (0.86), 7.708 (1.01), 7.715(1.52), 7.731 (1.58), 7.738 (1.88), 7.753 (1.14), 7.763 (0.78), 8.402(3.40), 8.424 (4.51), 8.532 (4.47), 8.555 (3.26), 8.836 (6.51), 10.001(3.82).

LC-MS (Method 3): R_(t)=2.01 min; MS (ESIpos): m/z=544 [M+H]⁺

Example 3951-(2-Chloro-4,6-difluorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-(4,4,4-trifluoro-2-methylbutan-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 30 mg (61 μmol) of the compound from Example 109A werereacted with 6.8 mg (67 μmol) of (4S)-4-hydroxypyrrolidin-2-one in thepresence of 13 mg (91 μmol) of potassium carbonate, 1.4 mg (6.1 μmol) ofpalladium(II) acetate and 7.0 mg (12 μmol) of Xantphos in 0.6 ml of1,4-dioxane. This was followed by dilution with 3.0 ml of acetonitrileand 2.0 ml of water. Separation was effected by means of preparativeHPLC (column: Chromatorex C18, 10 μm, 125×30 mm, solvent:acetonitrile/0.05% formic acid gradient; 0 to 3 min 15% acetonitrile, to15 min 90% acetonitrile and for a further 3 min 90% acetonitrile). Theproduct fractions were combined and purified again by means of normalphase chromatography (ethyl acetate-cyclohexane gradient). 14.2 mg (39%of theory, 93% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: −0.149 (0.54), −0.008 (6.50), 0.008(4.29), 0.146 (0.58), 1.234 (0.80), 1.259 (0.51), 1.501 (16.00), 2.328(0.70), 2.340 (1.32), 2.383 (1.47), 2.524 (2.20), 2.670 (0.66), 2.905(1.56), 2.920 (1.76), 2.948 (2.26), 2.963 (1.70), 3.393 (0.71), 3.423(0.92), 3.443 (0.90), 3.613 (0.70), 3.625 (0.94), 3.632 (0.70), 3.644(1.25), 3.655 (0.67), 3.662 (0.67), 3.674 (0.50), 4.271 (1.14), 5.318(3.02), 5.328 (2.85), 7.728 (0.46), 7.743 (0.94), 7.751 (0.83), 7.766(2.02), 7.777 (1.19), 7.789 (1.98), 7.799 (0.92), 8.507 (3.30), 8.529(3.96), 8.692 (4.75), 8.714 (3.70), 8.921 (7.11), 9.916 (3.82).

LC-MS (Method 1): R_(t)=1.03 min; MS (ESIpos): m/z=559 [M+H]⁺

Example 396N-(Bicyclo[1.1.1]pent-1-yl)-1-(2-chloro-4,6-difluorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 40 mg (92 μmol) of the compound from Example 133A werereacted with 13.2 mg (110 μmol) of bicyclo[1.1.1]pentan-1-aminehydrochloride in the presence of 41.9 mg (110 μmol) of HATU and 56 μl(0.32 mmol) of N,N-diisopropylethylamine in 0.56 ml ofdimethylformamide. The mixture was diluted with 0.1 ml of 1N aqueoushydrochloric acid, 1 ml of acetonitrile, 0.5 ml of DMSO and 0.5 ml ofdioxane and the solution was purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.1%formic acid gradient; 0 to 5 min 10% acetonitrile, over 14 min to 90%acetonitrile and for a further 4 min 90% acetonitrile). 34.9 mg (75% oftheory, 99% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.073 (0.76), 2.114 (16.00), 5.315(0.76), 5.319 (0.87), 5.324 (0.92), 5.329 (0.77), 7.770 (0.72), 7.793(0.74), 8.502 (1.41), 8.524 (1.80), 8.671 (1.71), 8.693 (1.35), 8.885(2.53), 10.018 (1.77).

LC-MS (Method 1): R_(t)=0.98 min; MS (ESIpos): m/z=501 [M+H]⁺

Example 3971-(2-Chloro-4,6-difluorophenyl)-N-(3-fluorobicyclo[1.1.1]pent-1-yl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 40 mg (92 μmol) of the compound from Example 133A werereacted with 15.2 mg (110 μmol) of 3-fluorobicyclo[1.1.1]pentan-1-aminehydrochloride in the presence of 41.9 mg (110 μmol) of HATU and 56 μl(0.32 mmol) of N,N-diisopropylethylamine in 0.56 ml ofdimethylformamide. The mixture was diluted with 0.1 ml of 1N aqueoushydrochloric acid, 1 ml of acetonitrile, 0.5 ml of DMSO and 0.5 ml ofdioxane and the solution was purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.1%formic acid gradient; 0 to 5 min 10% acetonitrile, over 14 min to 90%acetonitrile and for a further 4 min 90% acetonitrile). 28.0 mg (58% oftheory, 99% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: −0.008 (2.56), 0.008 (2.56), 2.114(2.50), 2.339 (3.23), 2.382 (3.75), 2.906 (2.85), 2.920 (2.97), 2.949(2.58), 2.964 (2.56), 3.389 (2.18), 3.419 (2.79), 3.442 (1.96), 3.611(1.42), 3.623 (1.89), 3.632 (1.95), 3.643 (2.76), 3.653 (1.35), 3.661(1.82), 3.674 (1.55), 4.272 (2.70), 4.281 (2.70), 5.317 (5.14), 5.322(4.81), 5.326 (5.55), 5.331 (4.14), 7.726 (0.85), 7.733 (1.24), 7.741(0.85), 7.748 (2.16), 7.757 (2.14), 7.763 (1.19), 7.771 (3.91), 7.782(2.76), 7.793 (4.22), 7.804 (2.14), 7.808 (1.69), 7.815 (1.12), 8.510(9.03), 8.533 (11.06), 8.678 (10.88), 8.701 (8.50), 8.926 (16.00),10.135 (10.20).

LC-MS (Method 1): R_(t)=0.96 min; MS (ESIpos): m/z=519 [M+H]⁺

Example 3981-(2-Chloro-4,6-difluorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Atropisomer Mixture)

According to GP1, 2.22 g (5.10 mmol) of the compound from Example 133Awere reacted with 1.00 g (6.11 mmol) of(2S)-1,1,1-trifluorobutan-2-amine hydrochloride in the presence of 2.91g (7.64 mmol) of HATU and 2.22 ml (12.7 mmol) ofN,N-diisopropylethylamine in 27.8 ml of dimethylformamide. To thereaction solution were added 200 ml of ice-water and 20 ml of 1N aqueoushydrochloric acid, and the precipitate was filtered off with suction anddried under high vacuum. 2.66 g (91% of theory, 95% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]=10.13 (d, 1H), 9.04 (s, 1H), 8.72 (d,1H), 8.54 (d, 1H), 7.82-7.72 (m, 2H), 5.33 (d, 1H), 4.84-4.70 (m, 1H),4.31-4.25 (m, 1H), 3.69-3.61 (m, 1H), 3.47-3.40 (m, 1H), 2.94 (dd, 1H),2.37 (d, 1H), 1.95-1.84 (m, 1H), 1.75-1.60 (m, 1H), 1.02-0.93 (m, 3H).

LC-MS (Method 4): R_(t)=3.18/3.20 min; MS (ESIpos): m/z=545 [M+H]⁺

2.66 g of the title compound (atropisomer mixture) were separated intothe atropisomers by chiral SFC (preparative SFC: column: DaicelChiralcel OX-H 5 m 250×30 mm; eluent: 0.0-5.5 min 74% carbon dioxide,26% acetonitrile; 6-12 min 61.1% carbon dioxide, 38.9% acetonitrile,12.5-14.0 min 74% carbon dioxide, 26% acetonitrile; temperature: 38° C.;flow rate: 180 ml/min; UV detection: 210 nm).

This gave (in the sequence of elution from the column) 857 mg ofatropisomer 1 from Example 399 (99% de) Rt=1.00 min and 977 mg (99% de)of atropisomer 2 from Example 400 R_(t)=2.10 min.

[Analytical SFC: column: Daicel Chiralpak OX-H 3 m 100×4.6 mm; eluent:80% carbon dioxide, 20% acetonitrile; temperature: 40° C.; flow rate: 3ml/min; UV detection: 210 nm]

Atropisomer 1 was finally suspended in 5 ml each of ethyl acetate andcyclohexane, the precipitate was filtered off and 494 mg (17.8% oftheory, 100% purity) of the compound from Example 399 were obtained.

Atropisomer 2 was finally suspended in 5 ml each of ethyl acetate andcyclohexane, the precipitate was filtered off and 852 mg (30.7% oftheory, 100% purity) of the compound from Example 400 were obtained. Themother liquor was concentrated to dryness by rotary evaporation andpurified by means of normal phase chromatography (cyclohexane-ethylacetate gradient), and a further 30.8 mg (1% of theory; 100% purity) ofthe compound from Example 400 were obtained.

Example 3991-(2-Chloro-4,6-difluorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Atropisomer 1)

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]=10.13 (d, 1H), 9.04 (s, 1H), 8.72 (d,1H), 8.54 (d, 1H), 7.83-7.72 (m, 2H), 5.33 (d, 1H), 4.83-4.71 (m, 1H),4.31-4.25 (m, 1H), 3.66 (dd, 1H), 3.41 (d, 1H), 2.94 (dd, 1H), 2.37 (d,1H), 1.96-1.83 (m, 1H), 1.74-1.59 (m, 1H), 0.98 (t, 3H).

LC-MS (Method 1): R_(t)=1.00 min; MS (ESIpos): m/z=545 [M+H]⁺

Example 4001-(2-Chloro-4,6-difluorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Atropisomer 2)

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]=10.13 (d, 1H), 9.04 (s, 1H), 8.73 (d,1H), 8.54 (d, 1H), 7.81-7.74 (m, 2H), 5.33 (d, 1H), 4.84-4.70 (m, 1H),4.32-4.24 (m, 1H), 3.64 (dd, 1H), 3.43 (d, 1H), 2.94 (dd, 1H), 2.37 (d,1H), 1.96-1.83 (m, 1H), 1.75-1.60 (m, 1H), 0.97 (t, 3H).

LC-MS (Method 1): R_(t)=1.01 min; MS (ESIpos): m/z=545 [M+H]⁺

Example 4011-(2-Chloro-4,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-N-(3-fluorobicyclo[1.1.1]pent-1-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 50.0 mg (99% purity, 113 μmol) of the compound fromExample 134A were reacted with 18.7 mg (136 μmol) of3-fluorobicyclo[1.1.1]pentan-1-amine hydrochloride in the presence of51.6 mg (136 μmol) of HATU and 69 μl (0.40 mmol) ofN,N-diisopropylethylamine in 1.2 ml of dimethylformamide. The mixturewas diluted with 1 ml of 1N aqueous hydrochloric acid and 2.0 ml of DMSOand the solution was purified by means of preparative HPLC (column:Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.1% formicacid gradient; 0 to 5 min 10% acetonitrile, over 14 min to 90%acetonitrile and for a further 4 min 90% acetonitrile). 51.4 mg (86% oftheory, 99% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: −0.008 (2.40), 0.008 (1.87), 2.073(14.92), 2.094 (8.32), 2.475 (2.00), 2.988 (1.30), 3.019 (2.12), 3.044(1.72), 3.178 (1.28), 3.201 (1.88), 3.331 (3.86), 3.587 (2.02), 3.607(1.63), 3.913 (3.18), 4.039 (3.15), 5.135 (3.79), 5.223 (3.55), 6.731(0.90), 6.741 (6.39), 6.754 (1.02), 6.763 (6.51), 7.677 (1.08), 7.689(1.56), 7.700 (2.08), 7.712 (2.36), 7.724 (2.95), 7.753 (2.13), 8.232(1.47), 8.237 (7.81), 8.259 (7.32), 8.599 (1.82), 8.641 (16.00), 10.305(0.96), 10.447 (8.86).

LC-MS (Method 3): R_(t)=1.62 min; MS (ESIpos): m/z=521 [M+H]⁺

Example 402N-(Bicyclo[1.1.1]pent-1-yl)-1-(2-chloro-4,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 50.0 mg (99% purity, 113 μmol) of the compound fromExample 134A were reacted with 16.2 mg (136 μmol) ofbicyclo[1.1.1]pentan-1-amine hydrochloride in the presence of 51.6 mg(136 μmol) of HATU and 69 μl (0.40 mmol) of N,N-diisopropylethylamine in1.2 ml of dimethylformamide. The mixture was diluted with 1 ml of 1Naqueous hydrochloric acid and 2.0 ml of DMSO and the solution waspurified by means of preparative HPLC (column: Chromatorex C18, 10 m,125×30 mm, solvent: acetonitrile/0.1% formic acid gradient; 0 to 5 min10% acetonitrile, over 14 min to 90% acetonitrile and for a further 4min 90% acetonitrile). 38.4 mg (67% of theory, 99% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.073 (2.07), 2.094 (16.00), 2.475(2.51), 5.132 (0.78), 6.731 (1.37), 6.754 (1.39), 8.232 (1.63), 8.254(1.55), 8.599 (2.96), 10.305 (1.69).

LC-MS (Method 3): R_(t)=1.64 min; MS (ESIpos): m/z=503 [M+H]⁺

Example 4037-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-4-oxo-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-1)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 100 mg (30% purity, 71.2 μmol) of the compound fromExample 121A were reacted with 10.9 mg (85.4 μmol) of1,1,1-trifluoro-2-methylpropan-2-amine in the presence of 32 mg (85μmol) of HATU and 31.0 μl (178 μmol) of N,N-diisopropylethylamine in0.72 ml of dimethylformamide. The mixture was diluted with 1 ml of 1Naqueous hydrochloric acid, water and 2.0 ml of DMSO and the solution waspurified by means of preparative HPLC (column: Chromatorex C18, 10 m,125×30 mm, solvent: acetonitrile/0.1% formic acid gradient; 0 to 5 min10% acetonitrile, over 14 min to 90% acetonitrile and for a further 4min 90% acetonitrile). 25.1 mg (66% of theory, 100% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.008 (0.97), 1.633 (16.00), 2.073(1.22), 3.051 (0.77), 3.083 (1.03), 3.225 (0.61), 3.235 (0.68), 3.257(0.51), 3.266 (0.48), 3.348 (0.96), 3.593 (0.55), 3.602 (0.62), 3.621(0.51), 3.630 (0.46), 3.925 (0.94), 4.047 (0.94), 5.135 (1.35), 5.143(1.37), 5.226 (1.35), 5.235 (1.32), 6.759 (1.96), 6.782 (2.01), 7.545(0.72), 7.565 (1.29), 7.585 (0.73), 8.266 (2.17), 8.289 (2.07), 8.739(3.38), 10.653 (2.85).

LC-MS (Method 3): R_(t)=1.71 min; MS (ESIpos): m/z=531 [M+H]⁺

Example 404 N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 100 mg (210 μmol) of the compound from Example 126Awere reacted with 23.4 mg (231 μmol) of (4S)-4-hydroxypyrrolidin-2-onein the presence of 43.6 mg (315 μmol) of potassium carbonate, 2.4 mg (11μmol) of palladium(II) acetate and 12 mg (21 μmol) of Xantphos in 1.9 mlof 1,4-dioxane. Subsequently, 100 mg of N-acetylcysteine were added andthe mixture was stirred at RT for 0.5 h. 20 ml of ethyl acetate wereadded, and the organic phase was extracted with saturated aqueous sodiumhydrogencarbonate solution, dried and concentrated. The residue waspurified by means of preparative HPLC (column: Chromatorex C18, 10 μm,125×30 mm, solvent: acetonitrile/0.05% formic acid gradient; 0 to 3 min.10% acetonitrile to 22 min. 55% acetonitrile, to 35 min. 65%acetonitrile and a further 3 min. 90% acetonitrile). 60.9 mg (53% oftheory, 99% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: −0.149 (1.32), −0.008 (11.84), 0.008(8.55), 0.146 (1.10), 0.342 (1.75), 0.561 (2.41), 0.578 (2.19), 0.659(1.53), 1.147 (2.63), 1.226 (1.75), 2.327 (1.75), 2.355 (2.41), 2.366(5.26), 2.399 (2.63), 2.670 (2.19), 2.710 (5.26), 2.916 (1.97), 2.930(2.19), 2.959 (1.97), 2.974 (1.75), 3.289 (16.00), 3.461 (2.63), 3.490(3.07), 3.672 (1.97), 3.684 (2.63), 3.701 (2.19), 3.714 (1.75), 4.286(1.75), 4.416 (1.53), 5.328 (5.26), 5.338 (5.26), 7.611 (2.63), 8.531(6.14), 8.554 (7.67), 8.709 (7.67), 8.731 (6.14), 9.062 (8.99), 10.247(3.29), 10.271 (3.07).

LC-MS (Method 1): R_(t)=1.04 min; MS (ESIpos): m/z=541 [M+H]⁺

Example 405N-[(1R)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[1-hydroxy-3-azabicyclo[3.1.0]hex-3-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP3, 150 mg (315 μmol) of the compound from Example 135Awere reacted with 51.7 mg (347 μmol, 91% purity) of3-azabicyclo[3.1.0]hexan-1-ol hydrochloride and 192 μl (1.10 μmol) ofN,N-diisopropylethylamine in 1.4 ml of dimethylformamide. The reactionsolution was diluted with 4 ml of acetonitrile and 0.5 ml of 1N aqueoushydrochloric acid and purified by means of preparative HPLC (column:Chromatorex C18, 10 m, 125×30 mm, solvent: acetonitrile/0.05% formicacid gradient; (0 to 3 min. 10% acetonitrile to 40 min. 90% acetonitrileand a further 3 min. 90% acetonitrile), and 118.6 mg (69% of theory, 99%purity) of the title compound were obtained.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=10.53 (d, 1H), 8.81 (s, 1H), 8.28 (d,1H), 7.64-7.50 (m, 2H), 6.84-6.69 (m, 1H), 6.08 (s, 0.5H), 5.96 (s,0.5H), 4.44-4.32 (m, 1H), 3.93-3.83 (m, 0.5H), 3.70-3.39 (m, 2H),3.21-3.08 (m, 1H), 1.70-1.51 (m, 1H), 1.26-1.14 (m, 1H), 1.07-0.98 (m,1H), 0.70-0.29 (m, 5H).

LC-MS (Method 3): R_(t)=2.05 min; MS (ESIpos) m/z 539 [M+H]⁺.

Example 4061-(2-Chloro-4,6-difluorophenyl)-7-[1-hydroxy-3-azabicyclo[3.1.0]hex-3-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP3, 150 mg (312 μmol) of the compound from Example 136Awere reacted with 51.2 mg (344 μmol, 91% purity) of3-azabicyclo[3.1.0]hexan-1-ol hydrochloride and 190 μl (1.09 mmol) ofN,N-diisopropylethylamine in 3 ml of dimethylformamide. The reactionsolution was diluted with 4 ml of acetonitrile and 1 ml of water andpurified by means of preparative HPLC (column: Chromatorex C18, 10 μm,125×30 mm, solvent: acetonitrile/0.05% formic acid gradient; (0 to 3min. 10% acetonitrile to 40 min. 90% acetonitrile and a further 3 min.90% acetonitrile), and 104.8 mg (61% of theory, 99% purity) of the titlecompound were obtained.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=10.41 (d, 1H), 8.77 (s, 1H), 8.28 (d,1H), 7.81-7.64 (m, 2H), 6.83-6.67 (m, 1H), 6.07 (s, 0.5H), 5.95 (s,0.5H), 4.80-4.67 (m, 1H), 3.93-3.82 (m, 0.5H), 3.71-3.39 (m, 2H),3.26-3.03 (m, 1.5H), 1.95-1.81 (m, 1H), 1.72-1.50 (m, 2H), 1.07-0.91 (m,4H), 0.49-0.37 (m, 1H).

LC-MS (Method 3): R_(t)=2.07 min; MS (ESIpos) m/z 543 [M+H]⁺.

Example 4071-(2-Chloro-4,6-difluorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 150 mg (312 μmol) of the compound from Example 136Awere reacted with 34.7 mg (344 μmol) of (4S)-4-hydroxypyrrolidin-2-onein the presence of 64.8 mg (469 μmol) of potassium carbonate, 7.0 mg (31μmol) of palladium(II) acetate and 36 mg (62 μmol) of Xantphos in 3.1 mlof 1,4-dioxane. This was followed by dilution with acetonitrile,filtration and concentration. The residue was dissolved in 3 ml ofacetonitrile and 0.5 ml of water and purified twice by means ofpreparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm, LM:acetonitrile/0.05% formic acid gradient; 0 to 3 min. 10% acetonitrile to35 min. 90% acetonitrile and a further 3 min. 90% acetonitrile, andcolumn: Chromatorex C18, 10 μm, 125×30 mm, LM: acetonitrile/0.05% formicacid gradient; 0 to 3 min. 10% acetonitrile to 24 min. 60% acetonitrile;to 35 min 65% acetonitrile, to 44 min 90% acetonitrile and a further 12min 90% acetonitrile). 91.2 mg (53% of theory, 99% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]=10.13 (d, 1H), 9.04 (s, 1H), 8.73 (d,1H), 8.54 (d, 1H), 7.83-7.72 (m, 2H), 5.33 (d, 1H), 4.83-4.71 (m, 1H),4.31-4.24 (m, 1H), 3.69-3.60 (m, 1H), 3.47-3.38 (m, 1H), 2.94 (dd, 1H),2.37 (d, 1H), 1.96-1.83 (m, 1H), 1.74-1.61 (m, 1H), 1.03-0.94 (m, 3H).

LC-MS (Method 1): R_(t)=1.07 min; MS (ESIpos): m/z=545 [M+H]⁺

Example 4081-(2-Chloro-4,6-difluorophenyl)-7-[1-hydroxy-3-azabicyclo[3.1.0]hex-3-yl]-4-oxo-N-[(2S)-1,1,1-trifluoropropan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP3, 150 mg (322 μmol) of the compound from Example 111Awere reacted with 52.7 mg (354 μmol, 91% purity) of3-azabicyclo[3.1.0]hexan-1-ol hydrochloride and 196 μl (1.13 mmol) ofN,N-diisopropylethylamine in 3.2 ml of dimethylformamide. The reactionsolution was diluted with 4 ml of acetonitrile and 0.5 ml of water andpurified by means of preparative HPLC (column: Chromatorex C18, 10 μm,125×30 mm, solvent: acetonitrile/0.05% formic acid gradient; (0 to 3min. 10% acetonitrile to 35 min. 90% acetonitrile and a further 3 min.90% acetonitrile), and 111.8 mg (65% of theory, 99% purity) of the titlecompound were obtained.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=10.46 (d, 1H), 8.76 (s, 1H), 8.27 (d,1H), 7.80-7.63 (m, 2H), 6.82-6.68 (m, 1H), 6.07 (s, 0.5H), 5.93 (s,0.5H), 4.94-4.82 (m, 1H), 3.92-3.81 (m, 0.5H), 3.70-3.39 (m, 2H),3.26-3.02 (m, 1.5H), 1.70-1.50 (m, 1H), 1.40-1.35 (m, 3H), 1.06-0.99 (m,1H), 0.47-0.38 (m, 1H).

LC-MS (Method 3): R_(t)=1.98 min; MS (ESIpos) m/z 529 [M+H]⁺.

Example 4091-(2-Chloro-4,6-difluorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2S)-1,1,1-trifluoropropan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 150 mg (322 μmol) of the compound from Example 111Awere reacted with 35.7 mg (354 μmol) of (4S)-4-hydroxypyrrolidin-2-onein the presence of 66.7 mg (483 μmol) of potassium carbonate, 7.2 mg (32μmol) of palladium(II) acetate and 37 mg (64 μmol) of Xantphos in 3.2 mlof 1,4-dioxane. This was followed by dilution with acetonitrile,filtration and concentration. The residue was dissolved in 3 ml ofacetonitrile and 0.5 ml of water and purified twice by means ofpreparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm, LM:acetonitrile/0.05% formic acid gradient; 0 to 3 min. 10% acetonitrile to35 min. 90% acetonitrile and a further 3 min. 90% acetonitrile, andcolumn: Chromatorex C18, 10 μm, 125×30 mm, LM: acetonitrile/0.05% formicacid gradient; 0 to 3 min. 10% acetonitrile to 24 min. 60% acetonitrile;to 35 min 65% acetonitrile, to 44 min 90% acetonitrile and a further 12min 90% acetonitrile). 55.7 mg (32% of theory, 98% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]=10.18 (d, 1H), 9.04 (d, 1H), 8.72 (d,1H), 8.54 (d, 1H), 7.82-7.72 (m, 2H), 5.33 (d, 1H), 4.98-4.86 (m, 1H),4.31-4.24 (m, 1H), 3.68-3.60 (m, 1H), 3.46-3.38 (m, 1H), 2.94 (dd, 1H),2.37 (d, 1H), 1.42-1.37 (m, 3H).

LC-MS (Method 1): R_(t)=1.01 min; MS (ESIpos): m/z=531 [M+H]⁺

Example 4107-[(4S)-4-Hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[1-(trifluoromethoxy)butan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP2, 188 mg (381 μmol) of the compound from Example 137Awere reacted with 38.5 mg (381 μmol) of (4S)-4-hydroxypyrrolidin-2-onein the presence of 79.0 mg (572 μmol) of potassium carbonate, 15 mg (69μmol) of palladium(II) acetate and 79.4 mg (137 μmol) of Xantphos in 3.8ml of 1,4-dioxane. This was followed by dilution with acetonitrile,filtration and concentration. The residue was dissolved in 3 ml ofacetonitrile and 0.5 ml of water and purified by means of preparativeHPLC (column: Chromatorex C18, 10 μm, 125×30 mm, solvent:acetonitrile/0.05% formic acid gradient; 0 to 3 min 10% acetonitrile, to35 min 90% acetonitrile and for a further 3 min 90% acetonitrile). 60.2mg (28% of theory, 100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]=9.81 (d, 1H), 8.99 (s, 1H), 8.71 (d,1H), 8.53 (d, 1H), 7.66-7.57 (m, 2H), 5.33 (d, 1H), 4.32-4.15 (m, 4H),3.69 (dd, 1H), 3.48 (d, 1H), 2.94 (dd, 1H), 2.37 (d, 1H), 1.75-1.54 (m,2H), 0.95 (t, 3H).

LC-MS (Method 3): R_(t)=1.92 min; MS (ESIpos): m/z=559 [M+H]⁺

60 mg of the title compound (diastereomer mixture) were separated intothe diastereomers by chiral HPLC (preparative HPLC: column: DaicelChiralcel OZ-H 5 μm 250×20 mm; eluent: 20% ethanol, 80% isohexane;temperature: 25° C.; flow rate: 20 ml/min; UV detection: 220 nm).

This gave (in the sequence of elution from the column) 10.1 mg ofdiastereomer 1 (99% de) R_(t)=1.77 min and 21 mg (98% de) ofdiastereomer 2 R_(t)=2.56 min.

[Analytical HPLC: column: Daicel Chiralpak OZ-3 3 μm 20×4.6 mm; eluent:80% ethanol, 50% isohexane; flow rate: 1 ml/min; UV detection: 220 nm]

Diastereomer 1 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90%acetonitrile and a further 3 min. 90% acetonitrile)), and 13.6 mg (6.3%of theory, 99% purity) of the title compound from Example 411 wereobtained.

Diastereomer 2 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90%acetonitrile and a further 3 min. 90% acetonitrile)), and 19.6 mg (9.1%of theory, 99% purity) of the title compound from Example 412 wereobtained.

Example 4117-[(4S)-4-Hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[1-(trifluoromethoxy)butan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]=9.81 (d, 1H), 8.99 (s, 1H), 8.71 (d,1H), 8.53 (d, 1H), 7.66-7.57 (m, 2H), 5.33 (d, 1H), 4.32-4.15 (m, 4H),3.69 (dd, 1H), 3.48 (d, 1H), 2.94 (dd, 1H), 2.37 (d, 1H), 1.76-1.55 (m,2H), 0.95 (t, 3H).

LC-MS (Method 3): R_(t)=1.90 min; MS (ESIpos): m/z=559 [M+H]⁺

Example 4127-[(4S)-4-Hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[1-(trifluoromethoxy)butan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2)

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]=9.81 (d, 1H), 8.99 (s, 1H), 8.71 (d,1H), 8.53 (d, 1H), 7.66-7.57 (m, 2H), 5.33 (d, 1H), 4.32-4.14 (m, 4H),3.69 (dd, 1H), 3.48 (d, 1H), 2.94 (dd, 1H), 2.37 (d, 1H), 1.75-1.54 (m,2H), 0.95 (t, 3H).

LC-MS (Method 3): R_(t)=1.89 min; MS (ESIpos): m/z=559 [M+H]⁺

Example 4131-(2-Chloro-4,6-difluorophenyl)-7-[1-hydroxy-3-azabicyclo[3.1.0]hex-3-yl]-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP3, 150 mg (312 μmol) of the compound from Example 108Cwere reacted with 51.2 mg (344 μmol, 91% purity) of3-azabicyclo[3.1.0]hexan-1-ol hydrochloride (Racemate) and 190 μl (1.09mmol) of N,N-diisopropylethylamine in 3.1 ml of dimethylformamide. Thereaction solution was diluted with 1 ml of acetonitrile and 0.5 ml ofwater and purified by means of preparative HPLC (column: ChromatorexC18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05% formic acid gradient;(0 to 3 min. 10% acetonitrile to 35 min. 90% acetonitrile and a further3 min. 90% acetonitrile), and 100.5 mg (59% of theory, 99% purity) ofthe title compound were obtained.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=10.42 (d, 1H), 8.76 (s, 1H), 8.28 (d,1H), 7.80-7.64 (m, 2H), 6.84-6.67 (m, 1H), 6.07 (s, 0.5H), 5.95 (s,0.5H), 4.80-4.66 (m, 1H), 3.93-3.82 (m, 0.5H), 3.71-3.38 (m, 2H),3.26-3.02 (m, 1.5H), 1.94-1.82 (m, 1H), 1.72-1.48 (m, 2H), 1.07-0.92 (m,4H), 0.48-0.37 (m, 1H).

LC-MS (Method 3): R_(t)=2.05 min; MS (ESIpos) m/z 543 [M+H]⁺.

Example 4141-(2-Chloro-4,6-difluorophenyl)-N-[(1R)-1-cyclopropyl-2,2,2-trifluoroethyl]-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 150 mg (305 μmol) of the compound from Example 138Awere reacted with 30.8 mg (305 μmol) of (4S)-4-hydroxypyrrolidin-2-onein the presence of 63.2 mg (457 μmol) of potassium carbonate, 12 mg (55μmol) of palladium(II) acetate and 63.5 mg (110 μmol) of Xantphos in 2.8ml of 1,4-dioxane. This was followed by dilution with acetonitrile,filtration and concentration. The residue was dissolved in 3 ml ofacetonitrile and 0.5 ml of water and purified twice by means ofpreparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm, LM:acetonitrile/0.05% formic acid gradient; 0 to 3 min. 10% acetonitrile to35 min. 90% acetonitrile and a further 3 min. 90% acetonitrile, andcolumn: Chromatorex C18, 10 μm, 125×30 mm, LM: acetonitrile/0.05% formicacid gradient; 0 to 3 min. 10% acetonitrile to 22 min. 55% acetonitrile;to 35 min 65% acetonitrile, and a further 3 min 90% acetonitrile).Product fractions from both runs were combined, concentrated andpurified once again by means of normal phase chromatography(dichloromethane-methanol gradient). 58 mg (34% of theory, 100% purity)of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]=10.27 (d, 1H), 9.03 (s, 1H), 8.73 (d,1H), 8.54 (d, 1H), 7.82-7.72 (m, 2H), 5.33 (d, 1H), 4.66-4.35 (m, 1H),4.31-4.25 (m, 1H), 3.69-3.61 (m, 1H), 3.46-3.39 (m, 1H), 2.94 (dd, 1H),2.37 (d, 1H), 1.28-1.19 (m, 1H), 0.71-0.51 (m, 3H), 0.39-0.31 (m, 1H).

LC-MS (Method 1): R_(t)=1.08 min; MS (ESIpos): m/z=557 [M+H]⁺

Example 4151-(2-Chloro-4,6-difluorophenyl)-N-[(1R)-1-cyclopropyl-2,2,2-trifluoroethyl]-7-[1-hydroxy-3-azabicyclo[3.1.0]hex-3-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP3, 150 mg (305 μmol) of the compound from Example 138Awere reacted with 49.9 mg (335 μmol, 91% purity) of3-azabicyclo[3.1.0]hexan-1-ol hydrochloride (racemate) and 186 μl (1.07mmol) of N,N-diisopropylethylamine in 1.4 ml of dimethylformamide. Thereaction solution was diluted with 4 ml of acetonitrile, filtered andpurified by means of preparative HPLC (column: Chromatorex C18, 10 m,125×30 mm, solvent: acetonitrile/0.05% formic acid gradient; (0 to 3min. 10% acetonitrile to 35 min. 90% acetonitrile and a further 3 min.90% acetonitrile), and 112 mg (66% of theory, 100% purity) of the titlecompound were obtained.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=10.55 (d, 1H), 8.76 (s, 1H), 8.29 (d,1H), 7.80-7.64 (m, 2H), 6.83-6.67 (m, 1H), 6.07 (s, 0.5H), 5.95 (s,0.5H), 4.45-4.29 (m, 1H), 3.93-3.82 (m, 0.5H), 3.71-3.38 (m, 2H),3.27-3.01 (m, 1.5H), 1.70-1.49 (m, 1H), 1.26-1.13 (m, 1H), 1.07-0.98 (m,1H), 0.71-0.29 (m, 5H).

LC-MS (Method 3): R_(t)=2.07 min; MS (ESIpos) m/z 555 [M+H]⁺.

Example 4167-[1-Hydroxy-3-azabicyclo[3.1.0]hex-3-yl]-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP3, 150 mg (323 μmol) of the compound from Example 115Awere reacted with 53.0 mg (356 μmol, 91% purity) of3-azabicyclo[3.1.0]hexan-1-ol hydrochloride (Racemate) and 197 μl (1.13mmol) of N,N-diisopropylethylamine in 1.5 ml of dimethylformamide. Thereaction solution was diluted with 0.5 ml of acetonitrile and purifiedby means of preparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm,solvent: acetonitrile/0.05% formic acid gradient; (0 to 3 min. 10%acetonitrile to 35 min. 90% acetonitrile and a further 3 min. 90%acetonitrile), and 116 mg (67% of theory, 99% purity) of the titlecompound were obtained.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=10.40 (d, 1H), 8.82 (s, 1H), 8.27 (d,1H), 7.65-7.49 (m, 2H), 6.83-6.69 (m, 1H), 6.08 (s, 0.5H), 5.96 (s,0.5H), 4.80-4.67 (m, 1H), 3.93-3.83 (m, 0.5H), 3.71-3.40 (m, 2H),3.20-3.07 (m, 1H), 1.94-1.81 (m, 1H), 1.71-1.49 (m, 2H), 1.07-0.91 (m,4H), 0.49-0.41 (m, 1H).

LC-MS (Method 3): R_(t)=2.03 min; MS (ESIpos) m/z 527 [M+H]⁺.

Example 4171-(2,6-Difluorophenyl)-7-[1-hydroxy-3-azabicyclo[3.1.0]hex-3-yl]-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP3, 100 mg (224 μmol) of the compound from Example 114Awere reacted with 50.1 mg (336 μmol, 91% purity) of3-azabicyclo[3.1.0]hexan-1-ol hydrochloride (Racemate) and 137 μl (785μmol) of N,N-diisopropylethylamine in 2.2 ml of dimethylformamide. Thereaction solution was diluted with 0.5 ml of acetonitrile and purifiedby means of preparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm,solvent: acetonitrile/0.05% formic acid gradient; (0 to 3 min. 10%acetonitrile to 35 min. 90% acetonitrile and a further 3 min. 90%acetonitrile), and 86.4 mg (75% of theory, 99% purity) of the titlecompound were obtained.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=10.41 (d, 1H), 8.76 (s, 1H), 8.28 (d,1H), 7.77-7.65 (m, 1H), 7.47-7.36 (m, 2H), 6.83-6.68 (m, 1H), 6.07 (s,0.5H), 5.93 (s, 0.5H), 4.81-4.67 (m, 1H), 3.93-3.81 (m, 0.5H), 3.71-3.39(m, 2H), 3.26-3.03 (m, 1.5H), 1.93-1.82 (m, 1H), 1.70-1.47 (m, 2H),1.06-0.92 (m, 4H), 0.48-0.37 (m, 1H).

LC-MS (Method 3): R_(t)=1.99 min; MS (ESIpos) m/z 509 [M+H]⁺.

Example 4181-(2-Chloro-4,6-difluorophenyl)-7-[3-methyl-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2S)-1,1,1-trifluoropropan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP2, 100 mg (215 μmol) of the compound from Example 111Awere reacted with 23.4 mg (236 μmol) of methylpyrrolidinone (racemate)in the presence of 44.5 mg (322 μmol) of potassium carbonate, 8.7 mg (39μmol) of palladium(II) acetate and 45 mg (77 μmol) of Xantphos in 2 mlof 1,4-dioxane. Subsequently, the mixture was acidified with 0.5 ml of1N aqueous hydrochloric acid and the mixture was concentrated. Theresidue was dissolved in 8 ml of dichloromethane and purified by meansof normal phase chromatography (ethyl acetate-cyclohexane gradient).78.9 mg (69% of theory, 99% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]=10.18 (d, 1H), 9.04-9.02 (m, 1H), 8.71(d, 1H), 8.55 (d, 1H), 7.80-7.70 (m, 2H), 4.97-4.86 (m, 1H), 3.59-3.49(m, 1H), 3.44-3.35 (m, 1H), 2.81-2.70 (m, 1H), 2.24-2.15 (m, 1H),1.67-1.55 (m, 1H), 1.43-1.36 (m, 3H), 1.17-1.11 (m, 3H).

LC-MS (Method 3): R_(t)=2.31 min; MS (ESIpos): m/z=529 [M+H]⁺

Example 4191-(2-Chloro-4,6-difluorophenyl)-4-oxo-7-(2-oxoimidazolidin-1-yl)-N-[(2S)-1-1,1,1-trifluoropropan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 100 mg (215 μmol) of the compound from Example 111Awere reacted with 92.3 mg (1.07 mmol) of imidazolidin-2-one in thepresence of 44.5 mg (322 μmol) of potassium carbonate, 2.4 mg (11 μmol)of palladium(II) acetate and 12 mg (21 μmol) of Xantphos in 6 ml of1,4-dioxane. Subsequently, the mixture was acidified with 1N aqueoushydrochloric acid and the mixture was concentrated. The residue wasdissolved in 8 ml of dichloromethane and purified by means of normalphase chromatography. 68.2 mg (59% of theory, 95% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]=10.28 (d, 1H), 8.96-8.94 (m, 1H), 8.56(d, 1H), 8.43 (d, 1H), 7.78-7.64 (m, 3H), 4.97-4.85 (m, 1H), 3.61-3.48(m, 2H), 1.42-1.35 (m, 3H).

LC-MS (Method 1): R_(t)=1.00 min; MS (ESIpos): m/z=516 [M+H]⁺

Example 420N-[(1R)-1-cyclopropyl-2,2,2-trifluoroethyl]-7-[4-methyl-2-oxopyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP2, 200 mg (420 μmol) of the compound from Example 126Awere reacted with 45.8 mg (462 μmol) of 4-methyl-2-pyrrolidinone(racemate) in the presence of 87.1 mg (631 μmol) of potassium carbonate,4.7 mg (21 μmol) of palladium(II) acetate and 24 mg (42 μmol) ofXantphos in 3.7 ml of 1,4-dioxane. Subsequently, the mixture wasacidified with 1N aqueous hydrochloric acid and the mixture wasconcentrated. The residue was dissolved in 8 ml of dichloromethane andpurified by means of normal phase chromatography (ethylacetate-cyclohexane gradient). The product fractions were combined andconcentrated. The residue was twice stirred in 10 ml of diethyl ether,decanted, dried under high vacuum and finally purified by means ofpreparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm, solvent:acetonitrile/0.05% formic acid gradient; 0 to 3 min 10% acetonitrile, to35 min 90% acetonitrile and for a further 3 min 90% acetonitrile). 159.5mg (70% of theory, 99% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]=10.26 (d, 1H), 9.06 (s, 1H), 8.71 (d,1H), 8.51 (d, 1H), 7.66-7.56 (m, 2H), 4.47-4.35 (m, 1H), 3.72 (dd, 1H),3.14 (dd, 1H), 2.73 (dd, 1H), 2.48-2.36 (m, 1H), 2.30 (dd, 1H),1.28-1.18 (m, 1H), 1.03 (d, 3H), 0.71-0.51 (m, 3H), 0.39-0.30 (m, 1H).

LC-MS (Method 3): R_(t)=2.30 min; MS (ESIpos): m/z=539 [M+H]⁺

Example 4211-(2-Chloro-4,6-difluorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2S)-1-(trifluoromethoxy)propan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 80.0 mg (161 μmol) of the compound from Example 112Awere reacted with 17.9 mg (177 μmol) of 4-(4S)-4-hydroxypyrrolidin-2-onein the presence of 33.4 mg (242 μmol) of potassium carbonate, 1.8 mg(8.1 μmol) of palladium(II) acetate and 9.3 mg (16 μmol) of Xantphos in1.6 ml of 1,4-dioxane. Subsequently, 80 mg of N-acetylcysteine wereadded and the mixture was stirred at RT for 0.5 h. 30 ml of ethylacetate were added, and the organic phase was washed with saturatedaqueous sodium hydrogencarbonate solution, dried over sodium sulphate,filtered and concentrated. The residue was purified by means ofpreparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm, solvent:acetonitrile/0.05% formic acid gradient; 0 to 3 min 10% acetonitrile, to35 min 90% acetonitrile and for a further 3 min 90% acetonitrile). 15.2mg (17% of theory, 100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]=9.85 (dd, 1H), 8.95 (s, 1H), 8.71 (d,1H), 8.52 (d, 1H), 7.82-7.71 (m, 2H), 5.33 (d, 1H), 4.42-4.14 (m, 4H),3.69-3.60 (m, 1H), 3.46-3.38 (m, 1H), 2.93 (dd, 1H), 2.37 (d, 1H), 1.27(dd, 3H).

LC-MS (Method 1): R_(t)=0.98 min; MS (ESIpos): m/z=561 [M+H]⁺

Example 4221-(2-Chloro-4,6-difluorophenyl)-7-[3-methyl-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP2, 100 mg (208 μmol) of the compound from Example 108Cwere reacted with 22.7 mg (229 μmol) of methylpyrrolidin-2-one(racemate) in the presence of 43.2 mg (312 μmol) of potassium carbonate,8.4 mg (37 μmol) of palladium(II) acetate and 43 mg (75 μmol) ofXantphos in 1.9 μl of 1,4-dioxane. Subsequently, the mixture wasacidified with 0.5 ml of 1N aqueous hydrochloric acid and the mixturewas concentrated. The residue was dissolved in 5 ml of dichloromethaneand purified by means of normal phase chromatography (ethylacetate-cyclohexane gradient). 67.5 mg (59% of theory, 99% purity) ofthe title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]=10.13 (d, 1H), 9.04 (s, 1H), 8.72 (d,1H), 8.55 (d, 1H), 7.80-7.70 (m, 2H), 4.84-4.70 (m, 1H), 3.60-3.48 (m,1H), 3.45-3.36 (m, 1H), 2.82-2.70 (m, 1H), 2.26-2.14 (m, 1H), 1.96-1.83(m, 1H), 1.75-1.54 (m, 2H), 1.14 (d, 3H), 1.02-0.94 (m, 3H).

LC-MS (Method 1): R_(t)=1.26 min; MS (ESIpos): m/z=543 [M+H]⁺

46 mg of the title compound (diastereomer mixture) were separated intothe diastereomers by chiral HPLC (preparative HPLC: column: DaicelChiralpak IF 5 μm 250×20 mm; eluent: 15% ethanol, 85% isohexane;temperature: 30° C.; flow rate: 15 ml/min; UV detection: 220 nm).

This gave (in the sequence of elution from the column) 35 mg ofdiastereomer 1 (Atropisomer Mixture) R_(t)=8.71 min and 16 mg (99% de,atropisomer mixture) of diastereomer 2 R_(t)=9.96/10.69 min.

[Analytical HPLC: column: Daicel Chiralpak IC 5 μm 250×4.6 mm; eluent:20% ethanol, 80% isohexane; flow rate: 1 ml/min; temp.: 30° C.; UVdetection: 220 nm]

Diastereomer 2 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90%acetonitrile and a further 3 min. 90% acetonitrile)), and 13.6 mg (12%of theory, 99% purity) of the title compound from Example 423 wereobtained.

Diastereomer 1 was purified once again by means of chiral preparativeHPLC (column: Daicel Chiralpak IC 5 μm 250×20 mm; eluent: 25% ethanol,75% isohexane; temperature: 25° C.; flow rate: 15 ml/min; UV detection:220 nm), and the following were obtained, in the sequence of elutionfrom the column: 10 mg of atropisomer 1 (99% de) R_(t)=10.21 min and 11mg (96% de) of atropisomer 2 R_(t)=11.11 min.

Atropisomer 1 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90%acetonitrile and a further 3 min. 90% acetonitrile)), and 7.8 mg (6.8%of theory, 99% purity) of the title compound from Example 424 wereobtained.

Atropisomer 2 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90%acetonitrile and a further 3 min. 90% acetonitrile)), and 7.9 mg (6.9%of theory, 99% purity) of the title compound from Example 425 wereobtained.

Example 4231-(2-Chloro-4,6-difluorophenyl)-7-[3-methyl-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2)

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]=10.13 (d, 1H), 9.04 (s, 1H), 8.72 (d,1H), 8.55 (d, 1H), 7.80-7.70 (m, 2H), 4.84-4.70 (m, 1H), 3.59-3.49 (m,1H), 3.44-3.35 (m, 1H), 2.82-2.70 (m, 1H), 2.25-2.14 (m, 1H), 1.96-1.84(m, 1H), 1.75-1.55 (m, 2H), 1.14 (d, 3H), 1.01-0.93 (m, 3H).

LC-MS (Method 1): R_(t)=1.25 min; MS (ESIpos): m/z=543 [M+H]⁺

Example 4241-(2-Chloro-4,6-difluorophenyl)-7-[3-methyl-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Atropisomer 1)

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]=10.13 (d, 1H), 9.04 (s, 1H), 8.72 (d,1H), 8.55 (d, 1H), 7.81-7.70 (m, 2H), 4.83-4.71 (m, 1H), 3.57-3.49 (m,1H), 3.45-3.35 (m, 1H), 2.81-2.71 (m, 1H), 2.25-2.14 (m, 1H), 1.95-1.84(m, 1H), 1.74-1.55 (m, 2H), 1.14 (d, 3H), 1.02-0.94 (m, 3H).

LC-MS (Method 1): R_(t)=1.26 min; MS (ESIpos): m/z=543 [M+H]⁺

Example 4251-(2-Chloro-4,6-difluorophenyl)-7-[3-methyl-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Atropisomer 2)

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]=10.13 (d, 1H), 9.03 (s, 1H), 8.72 (d,1H), 8.55 (d, 1H), 7.80-7.69 (m, 2H), 4.83-4.70 (m, 1H), 3.60-3.51 (m,1H), 3.42-3.35 (m, 1H), 2.82-2.70 (m, 1H), 2.25-2.14 (m, 1H), 1.97-1.84(m, 1H), 1.75-1.55 (m, 2H), 1.14 (d, 3H), 1.03-0.94 (m, 3H).

LC-MS (Method 1): R_(t)=1.26 min; MS (ESIpos): m/z=543 [M+H]⁺

Example 4261-(2,4-Difluorophenyl)-7-[2-methyl-5-oxopyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP2, 200 mg (449 μmol) of the compound from Example 67Awere reacted with 48.9 mg (494 μmol) of 5-methylpyrrolidin-2-one(racemate) in the presence of 93.0 mg (673 μmol) of potassium carbonate,5.0 mg (22 μmol) of palladium(II) acetate and 26 mg (45 μmol) ofXantphos in 4.4 ml of 1,4-dioxane. Subsequently, 80 mg ofN-acetylcysteine were added and the mixture was stirred at roomtemperature for a further 30 min. The reaction mixture was admixed with30 ml of ethyl acetate and washed with saturated aqueous sodiumhydrogencarbonate solution, dried over sodium sulphate, filtered andconcentrated. The residue was purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient; 0 to 3 min 10% acetonitrile, to 35 min 90%acetonitrile and for a further 3 min 90% acetonitrile). 120 mg (53% oftheory, 100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]=10.22 (d, 1H), 8.87 (t, 1H), 8.70 (dd,1H), 8.49 (dd, 1H), 7.93-7.84 (m, 1H), 7.68-7.60 (m, 1H), 7.41-7.33 (m,1H), 4.83-4.70 (m, 1H), 4.21-4.09 (m, 1H), 2.87-2.73 (m, 1H), 2.24-2.08(m, 1H), 1.96-1.84 (m, 1H), 1.73-1.59 (m, 2H), 1.07 (d, 1.5H), 0.98 (t,3H), 0.92 (d, 1.5H).

LC-MS (Method 1): R_(t)=1.17 min; MS (ESIpos): m/z=509 [M+H]⁺

120 mg of the title compound (diastereomer mixture) were separated intothe diastereomers by chiral HPLC (preparative HPLC: column: DaicelChiralpak AZ-H 5 μm 250×30 mm; eluent: 60% ethanol, 40% isohexane;temperature: 23° C.; flow rate: 50 ml/min; UV detection: 220 nm).

This gave (in the sequence of elution from the column) diastereomer 1(99% de) R_(t)=1.41 min and diastereomer 2 (99% de) R_(t)=2.24 min.

[Analytical HPLC: column: Daicel Chiralpak AZ-3 3 μm 50×4.6 mm; eluent:50% ethanol, 50% isohexane; flow rate: 1 ml/min; UV detection: 220 nm]

Diastereomer 1 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90%acetonitrile and a further 3 min. 90% acetonitrile)), and 41 mg (18% oftheory, 99% purity) of the title compound from Example 427 wereobtained.

Diastereomer 2 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90%acetonitrile and a further 3 min. 90% acetonitrile)), and 35.6 mg (16%of theory, 99% purity) of the title compound from Example 428 wereobtained.

Example 4271-(2,4-Difluorophenyl)-7-[2-methyl-5-oxopyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]=10.21 (d, 1H), 8.87 (s, 1H), 8.70 (dd,1H), 8.49 (dd, 1H), 7.92-7.84 (m, 1H), 7.68-7.60 (m, 1H), 7.40-7.33 (m,1H), 4.84-4.71 (m, 1H), 4.21-4.09 (m, 1H), 2.87-2.73 (m, 1H), 2.24-2.09(m, 1H), 1.95-1.83 (m, 1H), 1.73-1.60 (m, 2H), 1.07 (d, 1.5H), 0.98 (t,3H), 0.92 (d, 1.5H).

LC-MS (Method 1): R_(t)=1.17 min; MS (ESIpos): m/z=509 [M+H]⁺

Example 4281-(2,4-Difluorophenyl)-7-[2-methyl-5-oxopyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2)

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]=10.22 (d, 1H), 8.87 (d, 1H), 8.70 (dd,1H), 8.49 (dd, 1H), 7.93-7.83 (m, 1H), 7.67-7.60 (m, 1H), 7.41-7.33 (m,1H), 4.84-4.70 (m, 1H), 4.21-4.09 (m, 1H), 2.87-2.73 (m, 1H), 2.25-2.06(m, 1H), 1.96-1.84 (m, 1H), 1.74-1.59 (m, 2H), 1.08 (d, 1.5H), 0.98 (t,3H), 0.93 (d, 1.5H).

LC-MS (Method 1): R_(t)=1.17 min; MS (ESIpos): m/z=509 [M+H]⁺

Example 429 1-(2-Chloro-4,6-difluorophenyl)-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-7-[4-methyl-2-oxopyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP2, 200 mg (406 μmol) of the compound from Example 110Awere reacted with 44.3 mg (447 μmol) of 4-methylpyrrolidin-2-one(racemate) in the presence of 84.2 mg (609 μmol) of potassium carbonate,4.6 mg (20 μmol) of palladium(II) acetate and 24 mg (41 μmol) ofXantphos in 3.6 ml of 1,4-dioxane. Subsequently, the mixture wasacidified with 1N aqueous hydrochloric acid and the mixture wasconcentrated. The residue was dissolved in 8 ml of dichloromethane andpurified by means of normal phase chromatography (ethylacetate-cyclohexane gradient). 183 mg (80% of theory, 99% purity) of thetitle compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]=10.27 (d, 1H), 9.03 (s, 1H), 8.71 (d,1H), 8.51 (d, 1H), 7.81-7.71 (m, 2H), 4.47-4.33 (m, 1H), 3.71-3.62 (m,1H), 3.13-3.03 (m, 1H), 2.72 (dd, 1H), 2.46-2.36 (m, 1H), 2.29 (dd, 1H),1.29-1.18 (m, 1H), 1.01 (d, 3H), 0.72-0.51 (m, 3H), 0.40-0.30 (m, 1H).

LC-MS (Method 3): R_(t)=1.26 min; MS (ESIpos): m/z=555 [M+H]⁺

Example 4301-(2-Chloro-4,6-difluorophenyl)-7-[(2R)-2-(hydroxymethyl)-5-oxopyrrolidin-1-yl]-4-oxo-N-[(2)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 95.2 mg (198 μmol) of the compound from Example 108Cwere reacted with 50.0 mg (218 μmol) of the compound from Example 139Ain the presence of 41.1 mg (297 μmol) of potassium carbonate, 2.2 mg (10μmol) of palladium(II) acetate and 11 mg (20 μmol) of Xantphos in 2 mlof 1,4-dioxane. Subsequently, 100 mg of N-acetylcysteine were added andthe mixture was stirred at room temperature for a further 30 min. Thereaction mixture was admixed with 30 ml of ethyl acetate and washed withsaturated aqueous sodium hydrogencarbonate solution, dried overmagnesium sulphate, filtered and concentrated. The residue was purifiedby means of preparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm,solvent: acetonitrile/0.05% formic acid gradient; 0 to 3 min 10%acetonitrile, to 35 min 90% acetonitrile and for a further 3 min 90%acetonitrile). The product-containing fractions were combined and thesolvent was removed under reduced pressure. The residue was taken up in1.5 ml of THF and, while cooling with an ice bath, 57.5 mg (198 μmol) oftris(dimethylamino)sulphur trimethylsilyldifluoride were added. Themixture was stirred at room temperature for a further 1 h. 15 ml ofwater were added to the reaction solution, and the reaction solution wasextracted three times with 15 ml of ethyl acetate. The combined organicphases were washed with saturated aqueous sodium chloride solution,dried over magnesium sulphate, filtered and concentrated. 12 mg (10% oftheory, 90% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]=10.13 (dd, 1H), 9.05 (d, 1H), 8.71 (d,1H), 8.59 (d, 1H), 7.78-7.68 (m, 2H), 4.84-4.69 (m, 2H), 4.07-4.00 (m,1H), 3.51-3.40 (m, 1H), 3.22-3.11 (m, 0.5H), 2.81-2.69 (m, 1H),2.45-2.34 (m, 0.5H), 2.19-1.83 (m, 3H), 1.75-1.58 (m, 1H), 1.02-0.93 (m,3H).

LC-MS (Method 3): R_(t)=1.96/1.99 min; MS (ESIpos): m/z=559 [M+H]⁺

Example 4311-(2,4-Difluorophenyl)-7-[3-methyl-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP2, 150 mg (336 μmol) of the compound from Example 67Awere reacted with 36.7 mg (370 μmol) of 3-methylpyrrolidinone in thepresence of 69.8 mg (505 μmol) of potassium carbonate, 3.8 mg (17 μmol)of palladium(II) acetate and 19 mg (34 μmol) of Xantphos in 3.4 ml of1,4-dioxane. Subsequently, the reaction mixture was concentrated andadmixed with water and acidified with 1 M aqueous hydrochloric acid. Themixture was extracted three times with 20 ml of ethyl acetate. Thecombined organic phases were dried over magnesium sulphate, filtered andconcentrated by rotary evaporation. The residue was purified by means ofnormal phase chromatography (ethyl acetate-cyclohexane gradient). 113 mg(66% of theory, 100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]=10.22 (d, 1H), 8.85 (s, 1H), 8.70 (d,1H), 8.53 (dd, 1H), 7.91-7.82 (m, 1H), 7.66-7.57 (m, 1H), 7.40-7.32 (m,1H), 4.84-4.70 (m, 1H), 3.66-3.52 (m, 1H), 3.48-3.34 (m, 1H), 2.83-2.68(m, 1H), 2.26-2.15 (m, 1H), 1.95-1.84 (m, 1H), 1.73-1.52 (m, 2H),1.17-1.11 (m, 3H), 0.98 (t, 3H).

LC-MS (Method 3): R_(t)=2.32 min; MS (ESIpos): m/z=509 [M+H]⁺

Example 4321-(2,4-Difluorophenyl)-7-[4-methyl-2-oxoimidazolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

According to GP2, 250 mg (561 μmol) of the compound from Example 67Awere reacted with 61.7 mg (617 μmol) of 4-methylimidazolidin-2-one(racemate) in the presence of 116 mg (841 μmol) of potassium carbonate,6.3 mg (28 μmol) of palladium(II) acetate and 32 mg (56 μmol) ofXantphos in 5 ml of 1,4-dioxane. Subsequently, 250 mg ofN-acetylcysteine were added and the mixture was stirred at roomtemperature for a further 30 min. The reaction mixture was admixed with30 ml of ethyl acetate and washed with saturated aqueous sodiumhydrogencarbonate solution, dried over sodium sulphate, filtered andconcentrated. The residue was taken up in 4 ml of acetonitrile andpurified by means of preparative HPLC (column: Chromatorex C18, 10 μm,125×30 mm, solvent: acetonitrile/0.05% formic acid gradient; 0 to 3 min10% acetonitrile, to 35 min 90% acetonitrile and for a further 3 min 90%acetonitrile). Purification was additionally effected by means of normalphase chromatography (dichloromethane-methanol 95/5) and anotherpreparative HPLC.

35 mg of the crude product (diastereomer and regioisomer mixture) wereseparated into the regioisomers and diastereomers by chiral HPLC(preparative HPLC: column: Daicel Chiralpak AD-H 5 μm 250×20 mm; eluent:20% ethanol, 80% isohexane; temperature: 30° C.; flow rate: 15 ml/min;UV detection: 220 nm). [Analytical HPLC: column: Daicel Chiralpak IB 5μm 250×4.6 mm; eluent: 15% ethanol, 85% isohexane; flow rate: 1 ml/min;temp.: 25° C.; UV detection: 220 nm]

This gave (in the sequence of elution from the column) 10 mg of thetitle compound (Diastereomer 1 99% de) R_(t)=10.21 min, 10 mg ofdiastereomer 2 from Example 433 (99% de) R_(t)=12.52 min and 4 mg ofregiosisomer from Example 434 (Diastereomer Mixture) Rt=10.93/14.93 min.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]=10.31 (d, 1H), 8.78 (s, 1H), 8.56 (d,1H), 8.41 (d, 1H), 7.90-7.83 (m, 1H), 7.80 (br. s, 1H), 7.65-7.55 (m,1H), 7.39-7.31 (m, 1H), 4.83-4.69 (m, 1H), 3.81-3.65 (m, 2H), 3.14-3.03(m, 1H), 1.95-1.84 (m, 1H), 1.72-1.59 (m, 1H), 1.18-1.08 (m, 3H), 0.97(t, 3H).

LC-MS (Method 1): R_(t)=1.05 min; MS (ESIpos): m/z=510 [M+H]⁺

Example 4331-(2,4-Difluorophenyl)-7-[4-methyl-2-oxoimidazolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2)

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]=10.31 (d, 1H), 8.78 (s, 1H), 8.56 (d,1H), 8.41 (d, 1H), 7.91-7.82 (m, 1H), 7.80 (br. s, 1H), 7.66-7.55 (m,1H), 7.39-7.31 (m, 1H), 4.82-4.70 (m, 1H), 3.80-3.66 (m, 2H), 3.13-3.02(m, 1H), 1.95-1.84 (m, 1H), 1.72-1.60 (m, 1H), 1.18-1.07 (m, 3H), 0.97(t, 3H).

LC-MS (Method 1): R_(t)=1.05 min; MS (ESIpos): m/z=510 [M+H]⁺

Example 4341-(2,4-Difluorophenyl)-7-[5-methyl-2-oxoimidazolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

The title compound was obtained as a regioisomer from Example 432.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]=10.31 (d, 1H), 8.82-8.78 (m, 1H), 8.55(d, 1H), 8.42-8.36 (m, 1H), 7.92-7.83 (m, 1H), 7.66-7.57 (m, 2H),7.39-7.32 (m, 1H), 4.81-4.71 (m, 1H), 4.17-4.04 (m, 1H), 3.56-3.44 (m,1H), 2.91 (dd, 1H), 1.95-1.83 (m, 1H), 1.72-1.61 (m, 1H), 1.08 (d,1.5H), 0.98 (t, 3H), 0.92 (d, 1.5H).

LC-MS (Method 1): R_(t)=1.04 min; MS (ESIpos): m/z=510 [M+H]⁺

Example 435 N-[(1S)-1-Cyclopropyl-2,2-difluoroethyl]-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 40 mg (95 μmol) of the compound from Example 117A werereacted with 16.5 mg (105 μmol) of the compound from Example 140D in thepresence of 36 mg (95 μmol) of HATU and 40.0 μl (229 μmol) ofN,N-diisopropylethylamine in 0.55 ml of dimethylformamide. The reactionmixture was acidified with 1 ml of aqueous 1N hydrochloric acid, dilutedwith 1 ml of acetonitrile and purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.1%formic acid gradient; 0 to 5 min 10% acetonitrile, over 14 min to 90%acetonitrile and for a further 4 min 90% acetonitrile). 36.9 mg (72% oftheory, 97.5% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]=10.04 (d, 1H), 9.02 (s, 1H), 8.72 (d,1H), 8.54 (d, 1H), 7.66-7.56 (m, 2H), 6.25 (dt, 1H), 5.33 (d, 1H),4.32-4.26 (m, 1H), 4.03-3.88 (m, 1H), 3.70 (dd, 1H), 3.48 (d, 1H), 2.94(dd, 1H), 2.38 (d, 1H), 1.16-1.04 (m, 1H), 0.63-0.41 (m, 3H), 0.37-0.29(m, 1H).

LC-MS (Method 3): R_(t)=1.74 min; MS (ESIpos): m/z=523 [M+H]⁺.

Example 436 N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[5-methyl-2-oxo-1,3-oxazolidin-3-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP2, 50.0 mg (105 μmol) of the compound from Example 126Awere reacted with 12.8 mg (126 μmol) of 5-methyl-1,3-oxazolidin-2-one(racemate) in the presence of 21.8 mg (158 μmol) of potassium carbonate,2.4 mg (11 μmol) of palladium(II) acetate and 12 mg (21 μmol) ofXantphos in 0.7 ml of 1,4-dioxane. Subsequently, the mixture was dilutedwith 0.1 ml of 1N aqueous hydrochloric acid and 3 ml of acetonitrile andpurified by means of preparative HPLC (column: Chromatorex C18, 10 μm,125×30 mm, solvent: acetonitrile/0.05% formic acid gradient; 0 to 3 min10% acetonitrile, to 35 min 90% acetonitrile and for a further 3 min 90%acetonitrile). 40.4 mg (70% of theory, 99% purity) of the title compoundwere obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]=10.25 (d, 1H), 9.05 (s, 1H), 8.73 (d,1H), 8.34 (d, 1H), 7.64-7.53 (m, 2H), 4.83-4.73 (m, 1H), 4.46-4.34 (m,1H), 3.91 (dd, 1H), 1.36 (d, 3H), 1.29-1.19 (m, 1H), 0.71-0.52 (m, 3H),0.39-0.30 (m, 1H).

LC-MS (Method 3): R_(t)=2.18 min; MS (ESIpos): m/z=541 [M+H]⁺.

Example 437N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[(4R)-4-methyl-2-oxoimidazolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

To a solution of 168 mg (268 μmol) of the compound from Example 141B in5.9 ml of dimethylformamide were added, at room temperature, 37.0 mg(268 μmol) of potassium carbonate and 109 mg (699 μmol) of1,1′-carbonyldiimidazole. The mixture was stirred for a further 48 h.Subsequently, the mixture was diluted with 0.1 ml of 1N aqueoushydrochloric acid and 1 ml of acetonitrile and purified by means ofpreparative HPLC (column: Chromatorex C18, 10 m, 125×30 mm, solvent:acetonitrile/0.05% formic acid gradient; 0 to 3 min 10% acetonitrile, to35 min 90% acetonitrile and for a further 3 min 90% acetonitrile). 122mg (77% of theory, 99% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]=10.35 (d, 1H), 8.98 (s, 1H), 8.57 (d,1H), 8.44 (d, 1H), 7.83 (s, 1H), 7.63-7.54 (m, 2H), 4.46-4.34 (m, 1H),3.81-3.69 (m, 2H), 3.15-3.04 (m, 1H), 1.28-1.17 (m, 1H), 1.12 (d, 3H),0.71-0.50 (m, 3H), 0.39-0.30 (m, 1H).

LC-MS (Method 3): R_(t)=2.04 min; MS (ESIpos): m/z=540 [M+H]⁺.

Example 438N-[1-Cyclopropyl-3,3,3-trifluoropropyl]-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP1, 100 mg (237 μmol) of the compound from Example 121Awere reacted with 54.0 mg (285 μmol) of1-cyclopropyl-3,3,3-trifluoropropan-1-amine hydrochloride (racemate) inthe presence of 108 mg (285 μmol) of HATU and 104 μl (593 μmol) ofN,N-diisopropylethylamine in 2.4 ml of dimethylformamide. The mixturewas diluted with 2 ml of 1 M aqueous hydrochloric acid and 2 ml of DMSOand purified by means of preparative HPLC (column: Chromatorex C18, 10μm, 125×30 mm, solvent: acetonitrile/0.05% formic acid gradient; 0 to 3min 10% acetonitrile, to 15 min 90% acetonitrile and for a further 3 min90% acetonitrile). 111 mg (84% of theory, 100% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.14 (d, 1H), 8.70 (s, 1H), 8.27 (d,1H), 7.60-7.51 (m, 2H), 6.75 (d, 1H), 5.23 (d, 1H), 5.13 (d, 1H), 4.05(br. s, 1H), 3.92 (br. s, 1H), 3.84-3.73 (m, 1H), 3.65-3.56 (m, 1H),3.25 (dd, 1H), 3.07 (d, 1H), 2.85-2.59 (m, 2H), 1.21-1.10 (m, 1H),0.57-0.43 (m, 2H), 0.39-0.24 (m, 2H).

LC-MS (Method 1): R_(t)=0.91 min; 557 [M+H]⁺.

110 mg of the title compound (diastereomer mixture) were separated intothe diastereomers by chiral HPLC (preparative HPLC: column: DaicelChiralpak AD-H 5 μm 250×20 mm; eluent: 20% ethanol, 80% n-heptane;temperature: 23° C.; flow rate: 20 ml/min; UV detection: 220 nm).

This gave (in the sequence of elution from the column) 38.7 mg ofdiastereomer 1 (99% de) R_(t)=2.49 min and 41.0 mg (92% de) ofdiastereomer 2 R_(t)=3.09 min.

[Analytical HPLC: column: Daicel IE-3 5 μm 50×4.6 mm; eluent: 20%ethanol, 80% isohexane; UV detection: 220 nm].

Diastereomer 1 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.1%formic acid gradient; (0 to 5 min. 10% acetonitrile, over 14 min. to 90%acetonitrile and a further 4 min. 90% acetonitrile)), and 35.4 mg (27%of theory, 100% purity) of the title compound from Example 439 wereobtained.

Diastereomer 2 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.1%formic acid gradient; (0 to 5 min. 10% acetonitrile, over 14 min. to 90%acetonitrile and a further 4 min. 90% acetonitrile)), and 37.1 mg (28%of theory, 100% purity) of the title compound from Example 440 wereobtained.

Example 439N-[1-Cyclopropyl-3,3,3-trifluoropropyl]-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.14 (d, 1H), 8.70 (s, 1H), 8.27 (d,1H), 7.60-7.51 (m, 2H), 6.76 (d, 1H), 5.23 (d, 1H), 5.14 (d, 1H), 4.05(br. s, 1H), 3.92 (br. s, 1H), 3.84-3.74 (m, 1H), 3.65-3.57 (m, 1H),3.25 (dd, 1H), 3.06 (d, 1H), 2.85-2.60 (m, 2H), 1.20-1.10 (m, 1H),0.57-0.43 (m, 2H), 0.39-0.25 (m, 2H).

LC-MS (Method 1): R_(t)=0.90 min; 557 [M+H]⁺.

Example 440N-[1-Cyclopropyl-3,3,3-trifluoropropyl]-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.14 (d, 1H), 8.70 (s, 1H), 8.26 (d,1H), 7.60-7.51 (m, 2H), 6.76 (d, 1H), 5.23 (d, 1H), 5.14 (d, 1H), 4.05(br. s, 1H), 3.92 (br. s, 1H), 3.83-3.74 (m, 1H), 3.64-3.57 (m, 1H),3.25 (dd, 1H), 3.07 (d, 1H), 2.82-2.60 (m, 2H), 1.20-1.10 (m, 1H),0.57-0.43 (m, 2H), 0.39-0.25 (m, 2H).

LC-MS (Method 1): R_(t)=0.90 min; 557 [M+H]⁺.

Example 441N-[2-Cyclopropyl-1,1,1-trifluoropropan-2-yl]-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP1, 100 mg (237 μmol) of the compound from Example 121Awere reacted with 36.3 mg (237 μmol) of2-cyclopropyl-1,1,1-trifluoropropan-2-amine (racemate) in the presenceof 108 mg (285 μmol) of HATU and 104 μl (593 μmol) ofN,N-diisopropylethylamine in 3.3 ml of dimethylformamide. The mixturewas diluted with 1 ml of 1 M aqueous hydrochloric acid and 2 ml of DMSOand purified by means of preparative HPLC (column: Chromatorex C18, 10μm, 125×30 mm, solvent: acetonitrile/0.05% formic acid gradient; 0 to 3min 10% acetonitrile, to 15 min 90% acetonitrile and for a further 3 min90% acetonitrile). 71.1 mg (54% of theory, 100% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.38 (s, 1H), 8.73 (s, 1H), 8.28 (d,1H), 7.61-7.52 (m, 2H), 6.77 (d, 1H), 5.22 (d, 1H), 5.14 (d, 1H), 4.05(br. s, 1H), 3.92 (br. s, 1H), 3.61 (dd, 1H), 3.25 (dd, 1H), 3.07 (d,1H), 1.60 (s, 3H), 1.45-1.37 (m, 1H), 0.72-0.66 (m, 1H), 0.59-0.46 (m,3H).

LC-MS (Method 1): R_(t)=0.96 min; 557 [M+H]⁺.

70 mg of the title compound (diastereomer mixture) were separated intothe diastereomers by chiral HPLC (preparative HPLC: column: DaicelChiralpak IB 5 m 250×20 mm; eluent: 25% isopropanol, 75% n-heptane;temperature: 30° C.; flow rate: 15 ml/min; UV detection: 220 nm).

This gave (in the sequence of elution from the column) 33.0 mg ofdiastereomer 1 (99% de) R_(t)=4.61 min and 32.0 mg (98.5% de) ofdiastereomer 2 R_(t)=5.24 min.

[Analytical HPLC: column: Daicel Chiralpak IB 5 m 250×4.6 mm; eluent:30% isopropanol, 70% n-heptane; flow rate: 1.0 ml/min; temp.: 35° C.; UVdetection: 220 nm]

Diastereomer 1 was additionally obtained by means of preparative HPLC(0.1% formic acid; water-acetonitrile gradient), and 29.2 mg (22% oftheory, 100% purity) of the title compound from Example 442 wereobtained.

Diastereomer 2 was additionally obtained by means of preparative HPLC(0.1% formic acid; water-acetonitrile gradient), and 30.7 mg (23% oftheory, 100% purity) of the title compound from Example 443 wereobtained.

Example 442N-[2-Cyclopropyl-1,1,1-trifluoropropan-2-yl]-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.38 (s, 1H), 8.73 (s, 1H), 8.29 (d,1H), 7.61-7.51 (m, 2H), 6.77 (d, 1H), 5.23 (d, 1H), 5.14 (d, 1H), 4.05(br. s, 1H), 3.92 (br. s, 1H), 3.61 (dd, 1H), 3.25 (dd, 1H), 3.07 (d,1H), 1.60 (s, 3H), 1.45-1.36 (m, 1H), 0.73-0.65 (m, 1H), 0.60-0.45 (m,3H).

LC-MS (Method 3): R_(t)=1.82 min; 557 [M+H]⁺.

Example 443N-[2-Cyclopropyl-1,1-trifluoropropan-2-yl]-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.38 (s, 1H), 8.73 (s, 1H), 8.29 (d,1H), 7.61-7.51 (m, 2H), 6.76 (d, 1H), 5.23 (d, 1H), 5.14 (d, 1H), 4.05(br. s, 1H), 3.93 (br. s, 1H), 3.61 (dd, 1H), 3.25 (dd, 1H), 3.06 (d,1H), 1.60 (s, 3H), 1.46-1.37 (m, 1H), 0.73-0.64 (m, 1H), 0.61-0.45 (m,3H).

LC-MS (Method 3): R_(t)=1.82 min; 557 [M+H]⁺.

Example 444N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[(5R)-5-methyl-2-oxo-1,3-oxazolidin-3-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

To a solution of 137 mg (266 μmol) of the compound from Example 378 in5.9 ml of dimethylformamide were added, at room temperature, 108 mg (666μmol) of 1,1′-carbonyldiimidazole. The mixture was stirred for a further6 d. Subsequently, the mixture was diluted with 0.1 ml of 1N aqueoushydrochloric acid and 1 ml of acetonitrile and purified by means ofpreparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm, solvent:acetonitrile/0.05% formic acid gradient; 0 to 3 min 10% acetonitrile, to35 min 90% acetonitrile and for a further 3 min 90% acetonitrile). 90 mg(62% of theory, 99% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]=10.25 (d, 1H), 9.05 (s, 1H), 8.73 (d,1H), 8.34 (d, 1H), 7.65-7.53 (m, 2H), 4.83-4.73 (m, 1H), 4.47-4.35 (m,1H), 3.91 (dd, 1H), 1.37 (d, 3H), 1.29-1.18 (m, 1H), 0.72-0.52 (m, 3H),0.39-0.31 (m, 1H), a resonance under the water signal.

LC-MS (Method 3): R_(t)=2.20 min; MS (ESIpos): m/z=541 [M+H]⁺.

Example 445 N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[(5S)-5-methyl-2-oxo-1,3-oxazolidin-3-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

To a solution of 114 mg (222 μmol) of the compound from Example 142A in4.9 ml of dimethylformamide were added, at room temperature, 126 mg (775μmol) of 1,1′-carbonyldiimidazole. The mixture was stirred for a further7 d. Subsequently, the mixture was diluted with 0.1 ml of 1N aqueoushydrochloric acid and 1 ml of acetonitrile and purified by means ofpreparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm, solvent:acetonitrile/0.05% formic acid gradient; 0 to 3 min 10% acetonitrile, to35 min 90% acetonitrile and for a further 3 min 90% acetonitrile). 45.2mg (37% of theory, 99% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]=10.25 (d, 1H), 9.05 (s, 1H), 8.73 (d,1H), 8.34 (d, 1H), 7.64-7.54 (m, 2H), 4.83-4.73 (m, 1H), 4.47-4.34 (m,1H), 3.91 (dd, 1H), 1.37 (d, 3H), 1.29-1.19 (m, 1H), 0.71-0.52 (m, 3H),0.39-0.32 (m, 1H), a resonance under the water signal.

LC-MS (Method 1): R_(t)=1.18 min; MS (ESIpos): m/z=541 [M+H]⁺.

Example 446 N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[4-ethyl-2-oxotetrahydropyrimidin-1(2H)-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP2, 100 mg (210 μmol) of the compound from Example 126Awere reacted with 29.6 mg (231 μmol) of4-ethyltetrahydropyrimidin-2(1H)-one (racemate) in the presence of 43.6mg (315 μmol) of potassium carbonate, 4.7 mg (21 μmol) of palladium(II)acetate and 24 mg (42 μmol) of Xantphos in 2.1 ml of 1,4-dioxane.Subsequently, the mixture was diluted with 3 ml of acetonitrile and 2 mlof water and purified by means of preparative HPLC (column: ChromatorexC18, 10 m, 125×30 mm, solvent: acetonitrile/0.05% formic acid gradient;0 to 3 min 15% acetonitrile, to 15 min 90% acetonitrile and for afurther 3 min 90% acetonitrile). 24.3 mg (20% of theory, 100% purity) ofthe title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]=10.33 (d, 1H), 9.01 (s, 1H), 8.53 (d,1H), 8.31 (d, 1H), 7.64-7.54 (m, 2H), 7.40 (s, 1H), 4.46-4.34 (m, 1H),3.73-3.65 (m, 1H), 3.27-3.20 (m, 1H), 2.00-1.92 (m, 1H), 1.61-1.46 (m,2H), 1.41-1.18 (m, 2H), 0.85 (t, 3H), 0.71-0.51 (m, 3H), 0.39-0.31 (m,1H).

LC-MS (Method 3): R_(t)=2.15 min; MS (ESIpos): m/z=568 [M+H]⁺.

24 mg of the title compound (diastereomer mixture) were separated intothe diastereomers by chiral HPLC (preparative HPLC: column: DaicelChiralpak AZ-H 5 μm 250×30 mm; eluent: 50% ethanol, 50% n-heptane;temperature: 23° C.; flow rate: 50 ml/min; UV detection: 220 nm).

This gave (in the sequence of elution from the column) 5.6 mg ofdiastereomer 1 (compound 447, 99% de, 100% purity) R_(t)=1.23 min and9.9 mg (compound 448, 99% de, 100% purity) of diastereomer 2 R_(t)=1.63min.

[Analytical HPLC: column: Daicel Chiralpak AZ-3 3 μm 50×4.6 mm; eluent:50% ethanol, 50% isohexane; flow rate: 1.0 ml/min; UV detection: 220 nm]

Example 447 N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[4-ethyl-2-oxotetrahydropyrimidin-1(2H)-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]=10.33 (d, 1H), 9.01 (s, 1H), 8.53 (d,1H), 8.31 (d, 1H), 7.64-7.55 (m, 2H), 7.39 (s, 1H), 4.47-4.33 (m, 1H),3.75-3.64 (m, 1H), 3.28-3.20 (m, 1H), 2.01-1.90 (m, 1H), 1.61-1.45 (m,2H), 1.41-1.18 (m, 2H), 0.85 (t, 3H), 0.71-0.49 (m, 3H), 0.39-0.30 (m,1H).

LC-MS (Method 1): R_(t)=1.16 min; MS (ESIpos): m/z=568 [M+H]⁺.

Example 448 N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[4-ethyl-2-oxotetrahydropyrimidin-1(2H)-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2)

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]=10.33 (d, 1H), 9.01 (s, 1H), 8.53 (d,1H), 8.32 (d, 1H), 7.65-7.54 (m, 2H), 7.40 (s, 1H), 4.47-4.33 (m, 1H),3.74-3.65 (m, 1H), 3.28-3.20 (m, 1H), 2.00-1.91 (m, 1H), 1.61-1.45 (m,2H), 1.41-1.11 (m, 2H), 0.85 (t, 3H), 0.71-0.50 (m, 3H), 0.39-0.30 (m,1H).

LC-MS (Method 1): R_(t)=1.16 min; MS (ESIpos): m/z=568 [M+H]⁺.

Example 449 N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[(4S)-4-methyl-2-oxoimidazolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

To a solution of 184 mg (292 μmol) of the compound from Example 143B in6.4 ml of dimethylformamide were added, at room temperature, 40.4 mg(292 μmol) of potassium carbonate and 119 mg (731 μmol) of1,1′-carbonyldiimidazole. The mixture was stirred for a further 48 h.Subsequently, the mixture was diluted with 0.2 ml of 1N aqueoushydrochloric acid and 1 ml of acetonitrile and purified by means ofpreparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm, solvent:acetonitrile/0.1% formic acid gradient; 0 to 5 min 10% acetonitrile,over 14 min to 90% acetonitrile and for a further 4 min 90%acetonitrile). 111 mg (70% of theory, 99% purity) of the title compoundwere obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]=10.35 (d, 1H), 8.98 (s, 1H), 8.57 (d,1H), 8.44 (d, 1H), 7.83 (s, 1H), 7.63-7.53 (m, 2H), 4.47-4.34 (m, 1H),3.82-3.69 (m, 2H), 3.14-3.05 (m, 1H), 1.28-1.18 (m, 1H), 1.13 (d, 3H),0.71-0.50 (m, 3H), 0.39-0.30 (m, 1H).

LC-MS (Method 1): R_(t)=1.10 min; MS (ESIpos): m/z=540 [M+H]⁺.

Example 450 N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-4-oxo-7-(5-oxo-4,6-diazaspiro[2.4]hept-6-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

To a solution of 183 mg (243 μmol) of the compound from Example 144B in5.4 ml of dimethylformamide were added, at room temperature, 67.1 mg(486 μmol) of potassium carbonate and 98.5 mg (607 μmol) of1,1′-carbonyldiimidazole. The mixture was stirred for a further 6 h.Subsequently, the mixture was diluted with 0.2 ml of 1N aqueoushydrochloric acid and 1 ml of acetonitrile and purified by means ofpreparative HPLC (column: Chromatorex C18, 10 m, 125×30 mm, solvent:acetonitrile/0.1% formic acid gradient; 0 to 5 min 10% acetonitrile,over 14 min to 90% acetonitrile and for a further 4 min 90%acetonitrile). 116 mg (86% of theory, 99% purity) of the title compoundwere obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]=10.34 (d, 1H), 8.97 (s, 1H), 8.59 (d,1H), 8.45 (d, 1H), 7.90 (s, 1H), 7.59-7.50 (m, 2H), 4.47-4.34 (m, 1H),3.60 (s, 2H), 1.28-1.18 (m, 1H), 0.82-0.50 (m, 7H), 0.39-0.30 (m, 1H).

LC-MS (Method 3): R_(t)=2.08 min; MS (ESIpos): m/z=552 [M+H]⁺.

Example 451 N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-(4,4-dimethyl-2-oxoimidazolidin-1-yl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

To a solution of 190 mg (251 μmol) of the compound from Example 145B in5.5 ml of dimethylformamide were added, at room temperature, 69.4 mg(502 μmol) of potassium carbonate and 102 mg (628 μmol) of1,1′-carbonyldiimidazole. The mixture was stirred for a further 4 d.Another 1 equivalent each of 1,1′-carbonyldiimidazole and potassiumcarbonate were added and the mixture was stirred at room temperature fora further 48 h. Subsequently, the mixture was diluted with 25 ml of 0.5M aqueous hydrochloric acid and 50 ml of ethyl acetate. The phases wereseparated and the aqueous phase was extracted three times with 25 ml ofethyl acetate, dried over magnesium sulphate and filtered and thesolvent was removed under reduced pressure. The residue was taken up in0.2 ml of 1N aqueous hydrochloric acid and 1 ml of acetonitrile andpurified by means of preparative HPLC (column: Chromatorex C18, 10 μm,125×30 mm, solvent: acetonitrile/0.1% formic acid gradient; 0 to 5 min10% acetonitrile, over 14 min to 90% acetonitrile and for a further 4min 90% acetonitrile). 39.7 mg (28% of theory, 99% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]=10.35 (d, 1H), 8.98 (s, 1H), 8.57 (d,1H), 8.44 (d, 1H), 7.89 (s, 1H), 7.64-7.55 (m, 2H), 4.46-4.33 (m, 1H),1.28-1.14 (m, 7H), 0.70-0.50 (m, 3H), 0.39-0.29 (m, 1H).

LC-MS (Method 3): R_(t)=2.07 min; MS (ESIpos): m/z=554 [M+H]⁺.

Example 452N-(1,1-Difluoro-2-methylpropan-2-yl)-7-[(4R)-4-methyl-2-oxoimidazolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 100 mg (232 μmol, 97% purity) of the compound fromExample 146D were reacted with 40.5 mg (278 μmol) of1,1-difluoro-2-methylpropan-2-amine hydrochloride in the presence of 106mg (278 μmol) of HATU and 101 μl (580 μmol) of N,N-diisopropylethylaminein 6.2 ml of dimethylformamide. The mixture was diluted with 1 ml of 1 Maqueous hydrochloric acid and acetonitrile and purified by means ofpreparative HPLC (Chromatorex C18, 10 μm, 125×30 mm, solvent:acetonitrile/0.05% formic acid gradient; 0 to 3 min 10% acetonitrile, to15 min 90% acetonitrile and for a further 3 min 90% acetonitrile). 47 mg(40% of theory, 100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.12 (s, 1H), 8.90 (s, 1H), 8.55 (d,1H), 8.42 (d, 1H), 7.81 (s, 1H), 7.62-7.53 (m, 2H), 6.43 (t, 1H),3.80-3.69 (m, 2H), 3.14-3.05 (m, 1H), 1.45 (s, 6H), 1.12 (d, 3H).

LC-MS (Method 3): R_(t)=1.94 min; 510 [M+H]⁺.

Example 4537-[(4R)-4-Methyl-2-oxoimidazolidin-1-yl]-4-oxo-N-[(2S)-1-(trifluoromethoxy)butan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP1, 100 mg (232 μmol, 97% purity) of the compound fromExample 146D were reacted with 53.9 mg (278 μmol) of1-(trifluoromethoxy)butan-2-amine hydrochloride in the presence of 106mg (278 μmol) of HATU and 101 μl (580 μmol) of N,N-diisopropylethylaminein 2.3 ml of dimethylformamide. The mixture was adjusted to pH 1 with 1M aqueous hydrochloric acid, diluted with 20 ml of water and extractedthree times with 20 ml of ethyl acetate. The combined organic phaseswere washed with saturated aqueous sodium chloride solution, dried overmagnesium sulphate, filtered and concentrated. The residue was partlydissolved in acetonitrile, DMSO, dioxane and THF. The insolubleconstituents were filtered off with suction and corresponded to thetitle compound (109 mg, 84% of theory, 100% purity). The mother liquorwas purified by means of preparative HPLC (column: Chromatorex C18, 10μm, 125×30 mm, solvent: acetonitrile/0.05% formic acid gradient; 0 to 3min 10% acetonitrile, to 15 min 90% acetonitrile and for a further 3 min90% acetonitrile). The product fractions were combined, concentrated andlyophilized. 56.8 mg (44% of theory, 100% purity) of the title compoundwere obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=9.89 (d, 1H), 8.91 (s, 1H), 8.55 (d,1H), 8.42 (d, 1H), 7.82 (s, 1H), 7.64-7.52 (m, 2H), 4.26-4.13 (m, 3H),3.82-3.69 (m, 2H), 3.15-3.04 (m, 1H), 1.76-1.53 (m, 2H), 1.13 (d, 3H),0.95 (t, 3H).

LC-MS (Method 3): R_(t)=2.03 min; 558 [M+H]⁺.

166 mg of the title compound (diastereomer mixture) were separated intothe diastereomers by chiral HPLC (preparative HPLC: column: YMCChiralart Cellulose SA 5 μm 250×30 mm; eluent: 20% isopropanol, 80%n-heptane; temperature: 30° C.; flow rate: 30 ml/min; UV detection: 220nm).

This gave (in the sequence of elution from the column) 27 mg ofdiastereomer 1 (99% de) R_(t)=7.09 min and 28 mg (98% de) ofdiastereomer 2 R_(t)=7.87 min.

[Analytical HPLC: column: YMC Chiralart Amylose SA 5 μm 250×4.6 mm;eluent: 20% isopropanol, 80% n-heptane; flow rate: 1.0 ml/min; temp.:30° C.; UV detection: 220 nm]

Diastereomer 1 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.1%formic acid gradient; (0 to 5 min. 10% acetonitrile, over 14 min. to 90%acetonitrile and a further 4 min. 90% acetonitrile)), and 26.5 mg (20%of theory, 99% purity) of the title compound from Example 454 wereobtained.

Diastereomer 2 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.1%formic acid gradient; (0 to 5 min. 10% acetonitrile, over 14 min. to 90%acetonitrile and a further 4 min. 90% acetonitrile)), and 26.5 mg (20%of theory, 99% purity) of the title compound from Example 455 wereobtained.

Example 4547-[(4R)-4-Methyl-2-oxoimidazolidin-1-yl]-4-oxo-N-[(2S)-1-(trifluoromethoxy)butan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=9.89 (d, 1H), 8.91 (s, 1H), 8.55 (d,1H), 8.42 (d, 1H), 7.82 (s, 1H), 7.63-7.53 (m, 2H), 4.25-4.13 (m, 3H),3.80-3.69 (m, 2H), 3.14-3.05 (m, 1H), 1.75-1.53 (m, 2H), 1.12 (d, 3H),0.95 (t, 3H).

LC-MS (Method 3): R_(t)=2.04 min; 558 [M+H]⁺.

Example 4557-[(4R)-4-Methyl-2-oxoimidazolidin-1-yl]-4-oxo-N-[(2S)-1-(trifluoromethoxy)butan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=9.89 (d, 1H), 8.91 (s, 1H), 8.56 (d,1H), 8.42 (d, 1H), 7.82 (s, 1H), 7.63-7.52 (m, 2H), 4.26-4.14 (m, 3H),3.81-3.69 (m, 2H), 3.15-3.04 (m, 1H), 1.75-1.53 (m, 2H), 1.13 (d, 3H),0.95 (t, 3H).

LC-MS (Method 3): R_(t)=2.03 min; 558 [M+H]⁺.

Example 4567-[(4R)-4-Methyl-2-oxoimidazolidin-1-yl]-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 100 mg (232 μmol, 97% purity) of the compound fromExample 146D were reacted with 45.5 mg (278 μmol) of(2S)-1,1,1-trifluorobutan-2-amine hydrochloride in the presence of 106mg (278 μmol) of HATU and 101 μl (580 μmol) of N,N-diisopropylethylaminein 2.3 ml of dimethylformamide. The mixture was diluted with 1 ml of 1 Maqueous hydrochloric acid and acetonitrile and purified by means ofpreparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm, solvent:acetonitrile/0.05% formic acid gradient; 0 to 3 min 10% acetonitrile, to15 min 90% acetonitrile and for a further 3 min 90% acetonitrile). Theproduct fractions were combined, concentrated and lyophilized. 57.8 mg(47% of theory, 100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.21 (d, 1H), 8.99 (s, 1H), 8.56 (d,1H), 8.44 (d, 1H), 7.83 (s, 1H), 7.65-7.53 (m, 2H), 4.83-4.68 (m, 1H),3.81-3.68 (m, 2H), 3.16-3.03 (m, 1H), 1.96-1.82 (m, 1H), 1.74-1.58 (m,1H), 1.13 (d, 3H), 0.98 (t, 3H).

LC-MS (Method 3): R_(t)=2.00 min; 528 [M+H]⁺.

Example 4577-[(4R)-4-Methyl-2-oxoimidazolidin-1-yl]-4-oxo-N-(4,4,4-trifluoro-2-methylbutan-2-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 100 mg (232 μmol, 97% purity) of the compound fromExample 146D were reacted with 20.6 mg (116 μmol) of4,4,4-trifluoro-2-methylbutan-2-amine hydrochloride in the presence of106 mg (278 μmol) of HATU and 101 μl (580 μmol) ofN,N-diisopropylethylamine in 2.3 ml of dimethylformamide. The mixturewas diluted with 1 ml of 1 M aqueous hydrochloric acid and acetonitrileand purified by means of preparative HPLC (column: Chromatorex C18, 10m, 125×30 mm, solvent: acetonitrile/0.05% formic acid gradient; 0 to 3min 10% acetonitrile, to 15 min 90% acetonitrile and for a further 3 min90% acetonitrile). The product fractions were combined, concentrated andlyophilized. 49.8 mg (40% of theory, 100% purity) of the title compoundwere obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=9.98 (s, 1H), 8.88 (s, 1H), 8.54 (d,1H), 8.41 (d, 1H), 7.81 (s, 1H), 7.64-7.53 (m, 2H), 3.82-3.68 (m, 2H),3.14-3.05 (m, 1H), 2.96 (q, 2H), 1.49 (s, 6H), 1.13 (d, 3H).

LC-MS (Method 3): R_(t)=2.02 min; 542 [M+H]⁺.

Example 4587-[(4R)-4-Methyl-2-oxoimidazolidin-1-yl]-4-oxo-N-[3,3,4,4,4-pentafluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP1, 100 mg (232 μmol, 97% purity) of the compound fromExample 146D were reacted with 53.9 mg (278 μmol) of the compound fromExample 147B in the presence of 106 mg (278 μmol) of HATU and 101 μl(580 μmol) of N,N-diisopropylethylamine in 2.3 ml of dimethylformamide.The mixture was diluted with 1 ml of 1 M aqueous hydrochloric acid andacetonitrile and purified by means of preparative HPLC (column:Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05% formicacid gradient; 0 to 3 min 10% acetonitrile, to 15 min 90% acetonitrileand for a further 3 min 90% acetonitrile). The product fractions werecombined, concentrated and lyophilized. 52.6 mg (40% of theory, 100%purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.33 (d, 1H), 8.99 (s, 1H), 8.55 (d,1H), 8.44 (d, 1H), 7.83 (s, 1H), 7.63-7.53 (m, 2H), 5.11-4.95 (m, 1H),3.82-3.68 (m, 2H), 3.14-3.04 (m, 1H), 1.41 (d, 3H), 1.13 (d, 3H).

LC-MS (Method 3): R_(t)=2.05 min; 564 [M+H]⁺.

50 mg of the title compound (diastereomer mixture) were separated intothe diastereomers by chiral HPLC (preparative HPLC: column: DaicelChiralpak AD-H 5 μm 250×20 mm; eluent: 30% ethanol, 70% n-heptane;temperature: 25° C.; flow rate: 15 ml/min; UV detection: 210 nm).

This gave (in the sequence of elution from the column) 20.8 mg ofdiastereomer 1 (99% de) R_(t)=1.51 min and 20.2 mg (99% de) ofdiastereomer 2 R_(t)=2.09 min.

[Analytical HPLC: column: Daicel AD-3 3 μm 50×4.6 mm; eluent: 20%ethanol, 80% isohexane; UV detection: 220 nm].

Diastereomer 1 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.1%formic acid gradient; (0 to 2.5 min. 10% acetonitrile, over 15.5 min. to90% acetonitrile and a further 2 min. 90% acetonitrile)), and 19.1 mg(15% of theory, 100% purity) of the title compound from Example 459 wereobtained.

Diastereomer 2 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.1%formic acid gradient; (0 to 2.5 min. 10% acetonitrile, over 15.5 min. to90% acetonitrile and a further 2 min. 90% acetonitrile)), and 11.8 mg(9% of theory, 100% purity) of the title compound from Example 460 wereobtained.

Example 4597-[(4R)-4-Methyl-2-oxoimidazolidin-1-yl]-4-oxo-N-[3,3,4,4,4-pentafluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.33 (d, 1H), 8.99 (s, 1H), 8.55 (d,1H), 8.43 (d, 1H), 7.83 (s, 1H), 7.63-7.53 (m, 2H), 5.10-4.95 (m, 1H),3.80-3.69 (m, 2H), 3.15-3.05 (m, 1H), 1.41 (d, 3H), 1.13 (d, 3H).

LC-MS (Method 3): R_(t)=2.05 min; 564 [M+H]⁺.

Example 4607-[(4R)-4-Methyl-2-oxoimidazolidin-1-yl]-4-oxo-N-[3,3,4,4,4-pentafluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.33 (d, 1H), 8.99 (s, 1H), 8.55 (d,1H), 8.44 (d, 1H), 7.83 (s, 1H), 7.64-7.53 (m, 2H), 5.11-4.96 (m, 1H),3.81-3.69 (m, 2H), 3.14-3.03 (m, 1H), 1.41 (d, 3H), 1.12 (d, 3H).

LC-MS (Method 3): R_(t)=2.05 min; 564 [M+H]⁺.

Example 461 N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[4-fluoro-4-(hydroxymethyl)piperidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP3, 100 mg (210 μmol) of the compound from Example 126Awere reacted with 39.2 mg (231 μmol) of (4-fluoropiperidin-4-yl)methanolhydrochloride and 128 μl (736 μmol) of N,N-diisopropylethylamine in 2.1ml of dimethylformamide. The reaction solution was diluted withacetonitrile and 1 ml of 1N aqueous hydrochloric acid and purified bymeans of preparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm,solvent: acetonitrile/0.05% formic acid gradient; 0 to 3 min. 10%acetonitrile up to 15 min. to 90% acetonitrile and a further 3 min. 90%acetonitrile), and 102 mg (85% of theory, 100% purity) of the titlecompound were obtained.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=10.51 (d, 1H), 8.82 (s, 1H), 8.30 (d,1H), 7.61-7.52 (m, 2H), 7.19 (d, 1H), 4.96 (t, 1H), 4.44-4.32 (m, 1H),4.05-3.93 (m, 2H), 3.39 (dd, 2H), 3.24-3.10 (m, 2H), 1.78-1.47 (m, 4H),1.26-1.15 (m, 1H), 0.70-0.47 (m, 3H), 0.39-0.29 (m, 1H).

LC-MS (Method 3): R_(t)=2.01 min; MS (ESIpos) m/z 573 [M+H]⁺.

Example 462 N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[(2R)-2-(hydroxymethyl)piperidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP3, 100 mg (210 μmol) of the compound from Example 126Awere reacted with 35.1 mg (231 μmol) of (2R)-piperidin-2-ylmethanolhydrochloride and 128 μl (736 μmol) of N,N-diisopropylethylamine in 2.1ml of dimethylformamide. The reaction solution was diluted withacetonitrile and 1 ml of 1N aqueous hydrochloric acid and purified bymeans of preparative HPLC (column: Chromatorex C18, 10 m, 125×30 mm,solvent: acetonitrile/0.05% formic acid gradient; 0 to 3 min. 10%acetonitrile up to 15 min. to 90% acetonitrile and a further 3 min. 90%acetonitrile), and 74.1 mg (64% of theory, 100% purity) of the titlecompound were obtained.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=10.55 (d, 1H), 8.78 (s, 1H), 8.24 (d,1H), 7.60-7.48 (m, 2H), 7.10 (d, 1H), 4.74-4.63 (m, 1H), 4.44-4.32 (m,1H), 4.27-4.18 (m, 1H), 4.13-4.03 (m, 1H), 3.57-3.43 (m, 2H), 2.91-2.73(m, 1H), 1.82-1.72 (m, 1H), 1.64-1.40 (m, 4H), 1.36-1.14 (m, 2H),0.70-0.48 (m, 3H), 0.38-0.30 (m, 1H).

LC-MS (Method 3): R_(t)=2.14 min; MS (ESIpos) m/z 555 [M+H]⁺.

Example 463 N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[2-(hydroxymethyl)morpholin-4-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP3, 100 mg (210 μmol) of the compound from Example 126Awere reacted with 37.4 mg (231 μmol, 95% purity) ofmorpholin-2-ylmethanol hydrochloride and 128 μl (736 μmol) ofN,N-diisopropylethylamine in 2.1 ml of dimethylformamide. The reactionsolution was diluted with acetonitrile and 1 ml of 1N aqueoushydrochloric acid and purified by means of preparative HPLC (column:Chromatorex C18, m, 125×30 mm, solvent: acetonitrile/0.05% formic acidgradient; 0 to 3 min. 10% acetonitrile up to 15 min. to 90% acetonitrileand a further 3 min. 90% acetonitrile), and 102 mg (87% of theory, 100%purity) of the title compound were obtained.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=10.50 (d, 1H), 8.83 (s, 1H), 8.33 (d,1H), 7.59-7.48 (m, 2H), 7.12 (d, 1H), 4.78-4.71 (m, 1H), 4.44-4.32 (m,1H), 4.10 (d, 1H), 3.96 (d, 1H), 3.86 (d, 1H), 3.48-3.37 (m, 2H), 2.98(br. s, 1H), 2.72 (br. s, 1H), 1.26-1.15 (m, 1H), 0.71-0.48 (m, 3H),0.39-0.30.

LC-MS (Method 3): R_(t)=1.88 min; MS (ESIpos) m/z 557 [M+H]⁺.

100 mg of the title compound (diastereomer mixture) were separated intothe diastereomers by chiral HPLC (preparative HPLC: column: DaicelChiralpak ID 5 m 250×20 mm; eluent: 20% isopropanol, 80% n-heptane;temperature: 30° C.; flow rate: 15 ml/min; UV detection: 220 nm).

This gave (in the sequence of elution from the column) 45 mg ofdiastereomer 1 (99% de) R_(t)=13.46 min and 30 mg (99% de) ofdiastereomer 2 R_(t)=14.69 min.

[Analytical HPLC: column: Daicel Chiralpak ID 5 m 250×4.6 mm; eluent:20% isopropanol, 80% isohexane; flow rate: 1 ml/min; temp.: 30° C.; UVdetection: 220 nm]

Diastereomer 1 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.1%formic acid gradient; (0 to 5 min. 10% acetonitrile, over 14 min. to 90%acetonitrile and a further 4 min. 90% acetonitrile)), and 40.0 mg (34%of theory, 99% purity) of the title compound from Example 464 wereobtained.

Diastereomer 2 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.1%formic acid gradient; (0 to 5 min. 10% acetonitrile, over 14 min. to 90%acetonitrile and a further 4 min. 90% acetonitrile)), and 24.6 mg (21%of theory, 99% purity) of the title compound from Example 465 wereobtained.

Example 464 N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[2-(hydroxymethyl)morpholin-4-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=10.50 (d, 1H), 8.83 (s, 1H), 8.33 (d,1H), 7.59-7.48 (m, 2H), 7.12 (d, 1H), 4.78-4.72 (m, 1H), 4.44-4.32 (m,1H), 4.10 (d, 1H), 3.96 (d, 1H), 3.86 (d, 1H), 3.47-3.38 (m, 2H), 2.98(br. s, 1H), 2.72 (br. s, 1H), 1.26-1.16 (m, 1H), 0.70-0.48 (m, 3H),0.38-0.30.

LC-MS (Method 3): R_(t)=1.88 min; MS (ESIpos) m/z 557 [M+H]⁺.

Example 465 N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[2-(hydroxymethyl)morpholin-4-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2)

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=10.50 (d, 1H), 8.83 (s, 1H), 8.33 (d,1H), 7.59-7.48 (m, 2H), 7.12 (d, 1H), 4.78-4.71 (m, 1H), 4.45-4.32 (m,1H), 4.10 (d, 1H), 3.96 (d, 1H), 3.86 (d, 1H), 3.48-3.37 (m, 2H), 2.98(br. s, 1H), 2.72 (br. s, 1H), 1.26-1.15 (m, 1H), 0.71-0.48 (m, 3H),0.38-0.30.

LC-MS (Method 3): R_(t)=1.88 min; MS (ESIpos) m/z 557 [M+H]⁺.

Example 466 N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[(3R)-3-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 100 mg (210 μmol) of the compound from Example 126Awere reacted with 23.4 mg (231 μmol) of (3R)-3-hydroxypyrrolidin-2-onein the presence of 43.6 mg (315 μmol) of potassium carbonate, 4.7 mg (21μmol) of palladium(II) acetate and 24 mg (42 μmol) of Xantphos in 2.1 mlof 1,4-dioxane. Subsequently, the mixture was diluted with water andacetonitrile and purified by means of preparative HPLC (column:Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05% formicacid gradient; 0 to 3 min 15% acetonitrile, to 15 min 90% acetonitrileand for a further 3 min 90% acetonitrile). 58.1 mg (51% of theory, 100%purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]=10.25 (d, 1H), 9.07 (s, 1H), 8.74 (d,1H), 8.55 (d, 1H), 7.64-7.55 (m, 2H), 5.92 (d, 1H), 4.46-4.34 (m, 2H),3.63-3.53 (m, 1H), 2.37-2.27 (m, 1H), 1.84-1.71 (m, 1H), 1.29-1.19 (m,1H), 0.71-0.51 (m, 3H), 0.39-0.30 (m, 1H), a resonance partially underthe water signal.

LC-MS (Method 3): R_(t)=1.88 min; MS (ESIpos): m/z=541 [M+H]⁺.

Example 467 N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[(3S)-3-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 100 mg (210 μmol) of the compound from Example 126Awere reacted with 23.4 mg (231 μmol) of (3S)-3-hydroxypyrrolidin-2-onein the presence of 43.6 mg (315 μmol) of potassium carbonate, 4.7 mg (21μmol) of palladium(II) acetate and 24 mg (42 μmol) of Xantphos in 2.1 mlof 1,4-dioxane. Subsequently, the mixture was diluted with water andacetonitrile and purified by means of preparative HPLC (column:Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05% formicacid gradient; 0 to 3 min 15% acetonitrile, to 15 min 90% acetonitrileand for a further 3 min 90% acetonitrile). 62.1 mg (55% of theory, 100%purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]=10.25 (d, 1H), 9.07 (s, 1H), 8.74 (d,1H), 8.55 (d, 1H), 7.64-7.55 (m, 2H), 5.92 (d, 1H), 4.47-4.34 (m, 2H),3.61-3.54 (m, 1H), 2.38-2.27 (m, 1H), 1.84-1.71 (m, 1H), 1.29-1.18 (m,1H), 0.71-0.51 (m, 3H), 0.39-0.30 (m, 1H), a resonance partially underthe water signal.

LC-MS (Method 3): R_(t)=1.88 min; MS (ESIpos): m/z=541 [M+H]⁺.

Example 468 N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[3-(hydroxymethyl)-2-oxopyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP2, 57.3 mg (120 μmol) of the compound from Example 126Awere reacted with 30.4 mg (133 μmol) of the compound from Example 148Ain the presence of 24.9 mg (181 μmol) of potassium carbonate, 2.7 mg (12μmol) of palladium(II) acetate and 11 mg (24 μmol) of Xantphos in 3 mlof 1,4-dioxane. Subsequently, the mixture was diluted with 2 ml of waterand 3 ml of acetonitrile and purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05%formic acid gradient; 0 to 3 min 15% acetonitrile, to 15 min 90%acetonitrile and for a further 3 min 90% acetonitrile). The productfractions were concentrated and the residue was taken up in 3 ml of THF.The solution was admixed, while cooling with an ice bath, with 34.9 mg(120 μmol) of tris(dimethylamino)sulphur (trimethylsilyl)difluoride andstirred at 0-5° C. for 30 min and at room temperature for 1 h. Thereaction mixture was admixed with 10 ml of water and extracted threetimes with 15 ml of ethyl acetate. The combined organic phases werewashed with saturated aqueous sodium chloride solution, dried overmagnesium sulphate, filtered and concentrated. The residue was purifiedby means of preparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm,solvent: acetonitrile/0.05% formic acid gradient; 0 to 3 min 10%acetonitrile, to 35 min 90% acetonitrile and for a further 3 min 90%acetonitrile). The product fractions were combined, concentrated andlyophilized. Finally, the crude product was purified by means ofpreparative thin-layer chromatography (cyclohexane:ethyl acetate, 1:1,v/v). The product band was scraped off and the product was dissolved indichloromethane/methanol 9:1 (v/v), filtered and concentrated. Theresidue was taken up in dichloromethane, filtered through a fine filter,concentrated and lyophilized. 5 mg (7% of theory, 100% purity) of thetitle compound were obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]=10.26 (d, 1H), 9.06 (s, 1H), 8.72 (d,1H), 8.56 (d, 1H), 7.64-7.56 (m, 2H), 4.86 (br. s, 1H), 4.46-4.35 (m,1H), 3.76-3.70 (m, 1H), 3.63-33.54 (m, 2H), 3.52-3.44 (m, 1H), 2.85-2.78(m, 1H), 2.15-2.06 (m, 1H), 2.02-1.93 (m, 1H), 1.28-1.19 (m, 2H),0.70-0.52 (m, 3H), 0.38-0.31 (m, 1H).

LC-MS (Method 3): R_(t)=1.93 min; MS (ESIpos): m/z=555 [M+H]⁺.

Example 469N-tert-Butyl-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 50.0 mg (119 μmol) of the compound from Example 117Awere reacted with 10.5 mg (143 μmol) of tert-butylamine in the presenceof 54.4 mg (143 μmol) of HATU and 52.0 μl (298 μmol) ofN,N-diisopropylethylamine in 2.4 ml of dimethylformamide. The mixturewas diluted with 0.3 ml of 1 M aqueous hydrochloric acid and 1 ml ofacetonitrile and purified by means of preparative HPLC (column:Chromatorex C18, 10 m, 125×30 mm, solvent: acetonitrile/0.05% formicacid gradient; 0 to 5 min 10% acetonitrile, to 14 min 90% acetonitrileand for a further 4 min 90% acetonitrile). The product fractions werecombined, concentrated and lyophilized. 37.1 mg (65% of theory, 99%purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=9.70 (s, 1H), 8.92 (s, 1H), 8.69 (d,1H), 8.51 (d, 1H), 7.66-7.56 (m, 2H), 5.32 (d, 1H), 4.32-4.25 (m, 1H),3.69 (dd, 1H), 3.47 (d, 1H), 2.93 (dd, 1H), 2.37 (d, 1H), 1.41 (s, 9H).

LC-MS (Method 3): R_(t)=1.74 min; 475 [M+H]⁺.

Example 470N-[(1R)-1-Cyclopropylethyl]-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 50.0 mg (119 μmol) of the compound from Example 121Awere reacted with 12.1 mg (142 μmol) of (1R)-1-cyclopropylethanamine inthe presence of 54.1 mg (142 μmol) of HATU and 52.0 μl (297 μmol) ofN,N-diisopropylethylamine in 2.4 ml of dimethylformamide. The mixturewas diluted with 0.3 ml of 1 M aqueous hydrochloric acid and 1 ml ofacetonitrile and purified by means of preparative HPLC (column:Chromatorex C18, 10 m, 125×30 mm, solvent: acetonitrile/0.05% formicacid gradient; 0 to 2.5 min 10% acetonitrile, to 16 min 90% acetonitrileand for a further 2 min 90% acetonitrile). The product fractions werecombined, concentrated and lyophilized. 38.8 mg (67% of theory, 100%purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=9.95 (d, 1H), 8.67 (s, 1H), 8.26 (d,1H), 7.60-7.51 (m, 2H), 6.75 (d, 1H), 5.23 (d, 1H), 5.13 (d, 1H), 4.05(br. s, 1H), 3.92 (br. s, 1H), 3.65-3.47 (m, 2H), 3.25 (dd, 1H), 3.07(d, 1H), 1.22 (d, 3H), 1.03-0.93 (m, 1H), 0.51-0.38 (m, 2H), 0.33-0.20(m, 2H).

LC-MS (Method 3): R_(t)=1.50 min; 489 [M+H]⁺.

Example 471N-[1-Cyclobutylethyl]-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP1, 50.0 mg (119 μmol) of the compound from Example 117Awere reacted with 19.4 mg (143 μmol) of 1-cyclobutylethanaminehydrochloride (racemate) in the presence of 54.4 mg (143 μmol) of HATUand 73.0 μl (417 μmol) of N,N-diisopropylethylamine in 2.4 ml ofdimethylformamide. The mixture was diluted with 0.3 ml of 1 M aqueoushydrochloric acid and 1 ml of acetonitrile and purified by means ofpreparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm, solvent:acetonitrile/0.05% formic acid gradient; 0 to 5 min 10% acetonitrile, to14 min 90% acetonitrile and for a further 4 min 90% acetonitrile). Theproduct fractions were combined, concentrated and lyophilized. 30.7 mg(51% of theory, 99% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=9.61 (d, 1H), 8.96 (s, 1H), 8.70 (d,1H), 8.51 (d, 1H), 7.65-7.56 (m, 2H), 5.36-5.30 (m, 1H), 4.29 (br. s,1H), 4.07-3.95 (m, 1H), 3.69 (dd, 1H), 3.48 (d, 1H), 2.94 (dd, 1H),2.47-2.34 (m, 2H), 2.03-1.69 (m, 6H), 1.07 (d, 3H).

LC-MS (Method 3): R_(t)=1.86 min; 501 [M+H]⁺.

Example 4727-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-N-[(2S)-3-methylbutan-2-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 50.0 mg (119 μmol) of the compound from Example 121Awere reacted with 12.4 mg (142 μmol) of (2S)-3-methylbutan-2-amine inthe presence of 54.1 mg (142 μmol) of HATU and 52.0 μl (297 μmol) ofN,N-diisopropylethylamine in 2.4 ml of dimethylformamide. The mixturewas diluted with 0.3 ml of 1 M aqueous hydrochloric acid and 1 ml ofacetonitrile and purified by means of preparative HPLC (column:Chromatorex C18, 10 m, 125×30 mm, solvent: acetonitrile/0.05% formicacid gradient; 0 to 5 min 10% acetonitrile, to 14 min 90% acetonitrileand for a further 4 min 90% acetonitrile). 36.0 mg (61% of theory, 99%purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=9.96 (d, 1H), 8.67 (s, 1H), 8.27 (d,1H), 7.61-7.51 (m, 2H), 6.75 (d, 1H), 5.22 (d, 1H), 5.14 (d, 1H), 4.05(br. s, 1H), 3.96-3.86 (m, 2H), 3.61 (dd, 1H), 3.25 (dd, 1H), 3.07 (d,1H), 1.82-1.72 (m, 1H), 1.11 (d, 3H), 0.97-0.88 (m, 6H).

LC-MS (Method 3): R_(t)=1.57 min; 491 [M+H]⁺.

Example 4737-[(4S)-4-Hydroxy-2-oxopyrrolidin-1-yl]-N-[(2R)-3-methylbutan-2-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 50.0 mg (119 μmol) of the compound from Example 117Awere reacted with 12.5 mg (143 μmol) of (2R)-3-methylbutan-2-amine inthe presence of 54.4 mg (143 μmol) of HATU and 52.0 μl (298 μmol) ofN,N-diisopropylethylamine in 2.4 ml of dimethylformamide. The mixturewas diluted with 0.3 ml of 1 M aqueous hydrochloric acid and 1 ml ofacetonitrile and purified by means of preparative HPLC (column:Chromatorex C18, 10 m, 125×30 mm, solvent: acetonitrile/0.05% formicacid gradient; 0 to 5 min 10% acetonitrile, to 14 min 90% acetonitrileand for a further 4 min 90% acetonitrile). 41.7 mg (71% of theory, 99%purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=9.71 (d, 1H), 8.95 (s, 1H), 8.71 (d,1H), 8.52 (d, 1H), 7.66-7.56 (m, 2H), 5.33 (br. s, 1H), 4.29 (br. s,1H), 3.99-3.89 (m, 1H), 3.69 (dd, 1H), 3.48 (d, 1H), 2.94 (dd, 1H), 2.37(d, 1H), 1.85-1.74 (m, 1H), 1.13 (d, 3H), 0.98-0.89 (m, 6H).

LC-MS (Method 3): R_(t)=1.78 min; 489 [M+H]⁺.

Example 4747-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-N-(2,4-dimethylpentan-3-yl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 50.0 mg (119 μmol) of the compound from Example 121Awere reacted with 16.4 mg (142 μmol) of 2,4-dimethylpentan-3-amine inthe presence of 54.1 mg (142 μmol) of HATU and 52.0 μl (297 μmol) ofN,N-diisopropylethylamine in 2.4 ml of dimethylformamide. The mixturewas diluted with 0.3 ml of 1 M aqueous hydrochloric acid and 1 ml ofacetonitrile and purified by means of preparative HPLC (column:Chromatorex C18, 10 m, 125×30 mm, eluent: acetonitrile/0.05% formic acidgradient; 0 to 5 min 10% acetonitrile, to 14 min 90% acetonitrile andfor a further 4 min 90% acetonitrile). 37.8 mg (61% of theory, 99%purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=9.85 (d, 1H), 8.69 (s, 1H), 8.29 (d,1H), 7.61-7.51 (m, 2H), 6.75 (d, 1H), 5.23 (d, 1H), 5.14 (d, 1H), 4.05(br. s, 1H), 3.93 (br. s, 1H), 3.71-3.56 (m, 2H), 3.25 (dd, 1H), 3.07(d, 1H), 1.91-1.80 (m, 2H), 0.91-0.85 (m, 12H).

LC-MS (Method 1): R_(t)=0.94 min; 519 [M+H]⁺.

Example 475N-(2,4-Dimethylpentan-3-yl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 50.0 mg (119 μmol) of the compound from Example 117Awere reacted with 16.5 mg (143 μmol) of 2,4-dimethylpentan-3-amine inthe presence of 54.4 mg (143 μmol) of HATU and 52.0 μl (298 μmol) ofN,N-diisopropylethylamine in 2.4 ml of dimethylformamide. The mixturewas diluted with 0.3 ml of 1 M aqueous hydrochloric acid and 1 ml ofacetonitrile and purified by means of preparative HPLC (column:Chromatorex C18, 10 m, 125×30 mm, eluent: acetonitrile/0.05% formic acidgradient; 0 to 5 min 10% acetonitrile, to 14 min 90% acetonitrile andfor a further 4 min 90% acetonitrile). Finally, purification waseffected by means of normal phase chromatography (cyclohexane-ethylacetate gradient). 37.9 mg (61% of theory, 99% purity) of the titlecompound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=9.60 (d, 1H), 8.96 (s, 1H), 8.72 (d,1H), 8.52 (d, 1H), 7.66-7.56 (m, 2H), 5.33 (s, 1H), 4.29 (br. s, 1H),3.73-3.65 (m, 2H), 3.48 (d, 1H), 2.95 (dd, 1H), 2.37 (d, 1H), 1.93-1.81(m, 2H), 0.94-0.84 (m, 12H).

LC-MS (Method 3): R_(t)=1.99 min; 517 [M+H]⁺.

Example 476N-[1-Cyclobutylethyl]-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP1, 50.0 mg (119 μmol) of the compound from Example 121Awere reacted with 19.3 mg (142 μmol) of 1-cyclobutylethanaminehydrochloride (racemate) in the presence of 54.1 mg (142 μmol) of HATUand 72.0 μl (415 μmol) of N,N-diisopropylethylamine in 2.4 ml ofdimethylformamide. The mixture was diluted with 0.3 ml of 1 M aqueoushydrochloric acid and 1 ml of acetonitrile and purified by means ofpreparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm, solvent:acetonitrile/0.05% formic acid gradient; 0 to 5 min 10% acetonitrile, to14 min 90% acetonitrile and for a further 4 min 90% acetonitrile). 40.9mg (68% of theory, 99% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=9.86 (d, 1H), 8.68 (s, 1H), 8.27 (d,1H), 7.60-7.50 (m, 2H), 6.75 (d, 1H), 5.22 (br. s, 1H), 5.13 (br. s,1H), 4.08-3.89 (m, 3H), 3.65-3.55 (m, 1H), 3.25 (m, 1H), 3.07 (d, 1H),2.45-2.34 (m, 1H), 2.02-1.67 (m, 6H), 1.05 (d, 3H).

LC-MS (Method 3): R_(t)=1.64 min; 503 [M+H]⁺.

Example 477 N-[(1S)-1-Cyclopropylethyl]-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 50.0 mg (119 μmol) of the compound from Example 121Awere reacted with 12.1 mg (142 μmol) of (1S)-1-cyclopropylethanamine inthe presence of 54.1 mg (142 μmol) of HATU and 52.0 μl (297 μmol) ofN,N-diisopropylethylamine in 2.4 ml of dimethylformamide. The mixturewas diluted with 0.3 ml of 1 M aqueous hydrochloric acid and 1 ml ofacetonitrile and purified by means of preparative HPLC (column:Chromatorex C18, 10 m, 125×30 mm, solvent: acetonitrile/0.05% formicacid gradient; 0 to 2.5 min 10% acetonitrile, to 15.5 min 90%acetonitrile and for a further 2 min 90% acetonitrile). 38.9 mg (66% oftheory, 99% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=9.95 (d, 1H), 8.67 (s, 1H), 8.26 (d,1H), 7.60-7.51 (m, 2H), 6.75 (d, 1H), 5.22 (br. s, 1H), 5.13 (br. s,1H), 4.05 (br. s, 1H), 3.93 (br. s, 1H), 3.64-3.48 (m, 2H), 3.25 (m,1H), 3.07 (d, 1H), 1.22 (d, 3H), 1.03-0.93 (m, 1H), 0.51-0.39 (m, 2H),0.33-0.20 (m, 2H).

LC-MS (Method 3): R_(t)=1.50 min; 489 [M+H]⁺.

Example 478 N-[(1S)-1-Cyclopropylethyl]-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 50.0 mg (119 μmol) of the compound from Example 117Awere reacted with 12.2 mg (143 μmol) of (1S)-1-cyclopropylethanamine inthe presence of 54.4 mg (143 μmol) of HATU and 52.0 μl (298 μmol) ofN,N-diisopropylethylamine in 2.4 ml of dimethylformamide. The mixturewas diluted with 0.3 ml of 1 M aqueous hydrochloric acid and 1 ml ofacetonitrile and purified by means of preparative HPLC (column:Chromatorex C18, 10 m, 125×30 mm, solvent: acetonitrile/0.05% formicacid gradient; 0 to 2.5 min 10% acetonitrile, to 15.5 min 90%acetonitrile and for a further 2 min 90% acetonitrile). 26.5 mg (46% oftheory, 100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=9.70 (d, 1H), 8.94 (s, 1H), 8.69 (d,1H), 8.52 (d, 1H), 7.66-7.56 (m, 2H), 5.33 (d, 1H), 4.33-4.25 (m, 1H),3.69 (dd, 1H), 3.60-3.44 (m, 2H), 2.94 (dd, 1H), 2.37 (d, 1H), 1.24 (d,1H), 1.06-0.96 (m, 1H), 0.52-0.40 (m, 2H), 0.35-0.21 (m, 2H).

LC-MS (Method 3): R_(t)=1.70 min; 487 [M+H]⁺.

Example 479N-tert-Butyl-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 50.0 mg (119 μmol) of the compound from Example 121Awere reacted with 10.4 mg (142 μmol) of 2-methylpropan-2-amine in thepresence of 54.1 mg (142 μmol) of HATU and 52.0 μl (297 μmol) ofN,N-diisopropylethylamine in 2.4 ml of dimethylformamide. The mixturewas diluted with 0.3 ml of 1 M aqueous hydrochloric acid and 1 ml ofacetonitrile and purified by means of preparative HPLC (column:Chromatorex C18, 10 m, 125×30 mm, solvent: acetonitrile/0.05% formicacid gradient; 0 to 2.5 min 10% acetonitrile, to 15.5 min 90%acetonitrile and for a further 2 min 90% acetonitrile). 43.1 mg (76% oftheory, 100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=9.95 (s, 1H), 8.65 (s, 1H), 8.26 (d,1H), 7.60-7.51 (m, 2H), 6.74 (d, 1H), 5.22 (d, 1H), 5.13 (d, 1H), 4.04(br. s, 1H), 3.92 (br. s, 1H), 3.60 (dd, 1H), 3.24 (dd, 1H), 3.06 (d,1H), 1.39 (s, 9H).

LC-MS (Method 3): R_(t)=1.51 min; 477 [M+H]⁺.

Example 480N-[(1R)-1-Cyclopropylethyl]-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 50.0 mg (119 μmol) of the compound from Example 117Awere reacted with 12.2 mg (143 μmol) of (1R)-1-cyclopropylethanamine inthe presence of 54.4 mg (143 μmol) of HATU and 52.0 μl (298 μmol) ofN,N-diisopropylethylamine in 2.4 ml of dimethylformamide. The mixturewas diluted with 0.3 ml of 1 M aqueous hydrochloric acid and 1 ml ofacetonitrile and purified by means of preparative HPLC (column:Chromatorex C18, 10 m, 125×30 mm, solvent: acetonitrile/0.05% formicacid gradient; 0 to 2.5 min 10% acetonitrile, to 15.5 min 90%acetonitrile and for a further 2 min 90% acetonitrile). 25.7 mg (44% oftheory, 100% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=9.70 (d, 1H), 8.95 (s, 1H), 8.69 (d,1H), 8.52 (d, 1H), 7.65-7.57 (m, 2H), 5.33 (d, 1H), 4.32-4.26 (m, 1H),3.69 (dd, 1H), 3.59-3.44 (m, 2H), 2.94 (dd, 1H), 2.37 (d, 1H), 1.25 (d,1H), 1.05-0.96 (m, 1H), 0.53-0.40 (m, 2H), 0.35-0.21 (m, 2H).

LC-MS (Method 3): R_(t)=1.70 min; 487 [M+H]⁺.

Example 481N-(2-Cyclopropylpropan-2-yl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 50.0 mg (119 μmol) of the compound from Example 117Awere reacted with 14.2 mg (143 μmol) of 2-cyclopropylpropan-2-amine inthe presence of 54.4 mg (143 μmol) of HATU and 52.0 μl (298 μmol) ofN,N-diisopropylethylamine in 2.4 ml of dimethylformamide. The mixturewas diluted with 0.3 ml of 1 M aqueous hydrochloric acid and 1 ml ofacetonitrile and purified by means of preparative HPLC (column:Chromatorex C18, 10 μm, 125×30 mm, eluent: acetonitrile/0.05% formicacid gradient; 0 to 5 min 10% acetonitrile, to 14 min 90% acetonitrileand for a further 4 min 90% acetonitrile). 41.4 mg (69% of theory, 99%purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=9.71 (s, 1H), 8.92 (s, 1H), 8.70 (d,1H), 8.51 (d, 1H), 7.66-7.57 (m, 2H), 5.32 (d, 1H), 4.32-4.26 (m, 1H),3.69 (dd, 1H), 3.48 (d, 1H), 2.94 (dd, 1H), 2.37 (d, 1H), 1.33 (s, 6H),0.43 (s, 2H), 0.41 (s, 2H).

LC-MS (Method 3): R_(t)=1.87 min; 501 [M+H]⁺.

Example 4827-[(4S)-4-Hydroxy-2-oxopyrrolidin-1-yl]-N-[(2R)-3-methylbutan-2-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 50.0 mg (119 μmol) of the compound from Example 117Awere reacted with 12.5 mg (143 μmol) of (2S)-3-methylbutan-2-amine inthe presence of 54.4 mg (143 μmol) of HATU and 52.0 μl (298 μmol) ofN,N-diisopropylethylamine in 2.4 ml of dimethylformamide. The mixturewas diluted with 0.3 ml of 1 M aqueous hydrochloric acid and 1 ml ofacetonitrile and purified by means of preparative HPLC (column:Chromatorex C18, 10 m, 125×30 mm, solvent: acetonitrile/0.05% formicacid gradient; 0 to 5 min 10% acetonitrile, to 14 min 90% acetonitrileand for a further 4 min 90% acetonitrile). 37.4 mg (64% of theory, 99%purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=9.70 (d, 1H), 8.95 (s, 1H), 8.71 (d,1H), 8.52 (d, 1H), 7.66-7.57 (m, 2H), 5.33 (d, 1H), 4.32-4.26 (m, 1H),3.99-3.88 (m, 1H), 3.69 (dd, 1H), 3.48 (d, 1H), 2.94 (dd, 1H), 2.37 (d,1H), 1.84-1.74 (m, 1H), 1.12 (d, 3H), 0.98-0.89 (m, 6H).

LC-MS (Method 3): R_(t)=1.77 min; 489 [M+H]⁺.

Example 4837-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-N-[(2R)-3-methylbutan-2-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 50.0 mg (119 μmol) of the compound from Example 121Awere reacted with 12.4 mg (142 μmol) of (2R)-3-methylbutan-2-amine inthe presence of 54.1 mg (142 μmol) of HATU and 52.0 μl (297 μmol) ofN,N-diisopropylethylamine in 2.4 ml of dimethylformamide. The mixturewas diluted with 0.3 ml of 1 M aqueous hydrochloric acid and 1 ml ofacetonitrile and purified by means of preparative HPLC (0.05% formicacid, water-acetonitrile gradient). 30.1 mg (51% of theory, 99% purity)of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=9.96 (d, 1H), 8.68 (s, 1H), 8.27 (d,1H), 7.60-7.50 (m, 2H), 6.75 (d, 1H), 5.23 (d, 1H), 5.13 (d, 1H), 4.05(br. s, 1H), 3.97-3.86 (m, 2H), 3.61 (dd, 1H), 3.25 (dd, 1H), 3.07 (d,1H), 1.82-1.72 (m, 1H), 1.11 (d, 3H), 0.96-0.86 (m, 6H).

LC-MS (Method 3): R_(t)=1.56 min; 491 [M+H]⁺.

Example 4847-[(4S)-4-Hydroxy-2-oxopyrrolidin-1-yl]-N-[2-methylpentan-3-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP1, 100 mg (238 μmol) of the compound from Example 117Awere reacted with 39.4 mg (286 μmol) of 2-methylpentan-3-aminehydrochloride (racemate) in the presence of 109 mg (286 μmol) of HATUand 145 μl (835 μmol) of N,N-diisopropylethylamine in 4.6 ml ofdimethylformamide. The mixture was diluted with 0.3 ml of 1 M aqueoushydrochloric acid and 1 ml of acetonitrile and purified by means ofpreparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm, solvent:acetonitrile/0.05% formic acid gradient; 0 to 5.5 min 10% acetonitrile,to 34 min 90% acetonitrile and for a further 7.5 min 90% acetonitrile).83.4 mg (69% of theory, 99% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=9.61 (d, 1H), 8.95 (s, 1H), 8.71 (d,1H), 8.52 (d, 1H), 7.66-7.56 (m, 2H), 5.33 (d, 1H), 4.32-4.26 (m, 1H),3.87-3.77 (m, 1H), 3.69 (dd, 1H), 3.48 (d, 1H), 2.95 (dd, 1H), 2.37 (d,1H), 1.89-1.78 (m, 1H), 1.65-1.53 (m, 1H), 1.50-1.37 (m, 1H), 0.96-0.82(m, 9H).

LC-MS (Method 3): R_(t)=1.89 min; 503 [M+H]⁺. 80 mg of the titlecompound (diastereomer mixture) were separated into the diastereomers bychiral HPLC (preparative HPLC: column: Daicel Chiralcel OX-H 5 μm 250×20mm; eluent: 25% ethanol, 75% n-heptane; temperature: 23° C.; flow rate:30 ml/min; UV detection: 260 nm).

This gave (in the sequence of elution from the column) 30.7 mg ofdiastereomer 1 (99% de) R_(t)=4.00 min and 31.7 mg (99% de) ofdiastereomer 2 R_(t)=4.99 min.

[Analytical HPLC: column: Daicel OX-3 50×4.6 mm; eluent: 20% ethanol,80% isohexane; UV detection: 220 nm].

Diastereomer 1 was additionally obtained by means of preparative HPLC(water-acetonitrile gradient), and 29.8 mg (25% of theory, 99% purity)of the title compound from Example 485 were obtained.

Diastereomer 2 was additionally obtained by means of preparative HPLC(water-acetonitrile gradient), and 28.6 mg (24% of theory, 99% purity)of the title compound from Example 486 were obtained.

Example 4857-[(4S)-4-Hydroxy-2-oxopyrrolidin-1-yl]-N-[2-methylpentan-3-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=9.60 (d, 1H), 8.95 (s, 1H), 8.71 (d,1H), 8.52 (d, 1H), 7.66-7.56 (m, 2H), 5.33 (d, 1H), 4.32-4.26 (m, 1H),3.86-3.78 (m, 1H), 3.69 (dd, 1H), 3.48 (d, 1H), 2.94 (dd, 1H), 2.37 (d,1H), 1.89-1.78 (m, 1H), 1.65-1.53 (m, 1H), 1.50-1.37 (m, 1H), 0.96-0.83(m, 9H).

LC-MS (Method 3): R_(t)=1.91 min; 503 [M+H]⁺.

Example 4867-[(4S)-4-Hydroxy-2-oxopyrrolidin-1-yl]-N-[2-methylpentan-3-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=9.60 (d, 1H), 8.95 (s, 1H), 8.71 (d,1H), 8.52 (d, 1H), 7.66-7.57 (m, 2H), 5.33 (d, 1H), 4.32-4.26 (m, 1H),3.87-3.78 (m, 1H), 3.69 (dd, 1H), 3.48 (d, 1H), 2.94 (dd, 1H), 2.37 (d,1H), 1.88-1.78 (m, 1H), 1.65-1.53 (m, 1H), 1.50-1.37 (m, 1H), 0.95-0.84(m, 9H).

LC-MS (Method 3): R_(t)=1.91 min; 503 [M+H]⁺.

Example 4877-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-N-[2-methylpentan-3-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP1, 100 mg (237 μmol) of the compound from Example 121Awere reacted with 39.2 mg (285 μmol) of 2-methylpentan-3-aminehydrochloride (racemate) in the presence of 108 mg (285 μmol) of HATUand 145 μl (835 μmol) of N,N-diisopropylethylamine in 4.6 ml ofdimethylformamide. The mixture was diluted with 0.3 ml of 1 M aqueoushydrochloric acid and 1 ml of acetonitrile and purified by means ofpreparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm, solvent:acetonitrile/0.05% formic acid gradient; 0 to 5 min 10% acetonitrile, to14 min 90% acetonitrile and for a further 4 min 90% acetonitrile). 80.7mg (67% of theory, 99% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=9.86 (d, 1H), 8.68 (s, 1H), 8.28 (d,1H), 7.60-7.51 (m, 2H), 6.75 (d, 1H), 5.23 (d, 1H), 5.13 (d, 1H), 4.05(br. s, 1H), 3.92 (br. s, 1H), 3.84.3.75 (m, 1H), 3.61 (dd, 1H), 3.25(dd, 1H), 3.07 (d, 1H), 1.87-1.76 (m, 1H), 1.63-1.51 (m, 1H), 1.48-1.35(m, 1H), 0.94-0.84 (m, 9H).

LC-MS (Method 3): R_(t)=1.69 min; 505 [M+H]⁺.

Example 4887-[(3R)-3-Hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 63.0 mg (150 μmol) of the compound from Example 149Awere reacted with 21.0 mg (165 μmol) of1,1,1-trifluoro-2-methylpropan-2-amine in the presence of 68.6 mg (180μmol) of HATU and 65.0 μl (376 μmol) of N,N-diisopropylethylamine in 2.1ml of dimethylformamide. The mixture was diluted with 0.1 ml of 1 Maqueous hydrochloric acid and 1 ml of acetonitrile and purified by meansof preparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm, solvent:acetonitrile/0.05% formic acid gradient; 0 to 5 min 10% acetonitrile, to14 min 90% acetonitrile and for a further 4 min 90% acetonitrile). 64.8mg (81% of theory, 99% purity) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.34 (s, 1H), 9.02 (s, 1H), 8.74 (d,1H), 8.54 (d, 1H), 7.64-7.54 (m, 2H), 5.91 (d, 1H), 4.43-4.35 (m, 1H),3.62-3.54 (m, 1H), 2.38-2.27 (m, 1H), 1.83-1.70 (m, 1H), 1.65 (s, 6H).

LC-MS (Method 3): R_(t)=1.91 min; 529 [M+H]⁺.

Example 4897-[4,4-Bis(hydroxymethyl)piperidin-1-yl]-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphlthyridine-3-carboxamide

The compound from Example 126A (60.0 mg, 126 μmol) was initially chargedin 1.3 ml of DMF, 4,4-piperidinediyldimethanol hydrochloride (32 mg, 177μmol) and N,N-diisopropylethylamine (99 μl, 567 μmol) were added, andthe mixture was stirred at room temperature overnight. The reactionsolution was admixed with acetonitrile/water/TFA and purified by meansof preparative HPLC (RP18 column, eluent: acetonitrile/water gradientwith addition of 0.1% TFA). The product fractions were concentrated, andthe residue was dissolved in dichloromethane and washed twice withsaturated aqueous sodium hydrogencarbonate solution. The combinedaqueous phases were re-extracted once with dichloromethane. The combinedorganic phases were dried over sodium sulphate, filtered andconcentrated by rotary evaporation. This gave 67 mg of the targetcompound (89% of theory, purity 98%).

LC-MS (Method 3): R_(t)=1.83 min; MS (ESIpos): m/z=585 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.008 (0.91), 0.006 (0.40), 0.008(0.59), 1.334 (0.64), 2.519 (0.77), 2.524 (0.69), 3.276 (1.91), 3.290(1.96), 3.310 (16.00), 3.475 (0.57), 4.399 (0.74), 4.412 (1.55), 4.426(0.61), 7.078 (0.69), 7.101 (0.69), 7.542 (0.48), 7.564 (0.88), 7.586(0.48), 8.244 (0.95), 8.267 (0.87), 8.792 (1.45), 10.539 (0.54), 10.562(0.51).

In analogy to Example 489, the example compounds shown in Table 23 wereprepared by reacting the respected starting compounds Example 126A orExample 115A with the appropriate amines (or salts thereof; 1.2-4equivalents) under the reaction conditions described (1.5 h to 18 h atroom temperature).

TABLE 23 IUPAC name LC-MS method Structure Retention time Amine usedMass detected Ex. Yield NMR data 490

LC-MS (Method 3): R_(t) = 1.34 min m/z = 540 [M + H]⁺ ¹H-NMR (400 MHz,DMSO-d₆) δ [ppm]: 0.008 (2.50), 0.320 (0.77), 0.330 (1.18), 0.343(1.15), 0.355 (0.91), 0.366 (0.44), 0.511 (0.83), 0.523 (1.21), 0.535(1.10), 0.547 (1.19), 0.555 (0.93), 0.566 (1.24), 0.577 (1.01), 0.587(0.92), 0.597 (0.75), 0.611 (0.46), 0.626 (0.65), 0.636 (0.63), 0.647(1.12), 0.657 (0.98), 0.663 (0.93), 0.670 (0.89), 0.678 (0.44), 1.177(0.50), 1.185 (0.71), 1.197 (1.20), 1.206 (0.87), 1.217 (1.15), 1.229(0.69), 1.238 (0.50), 2.073 (0.92), 2.159 (16.00), 2.276 (3.99), 2.288(5.69), 2.299 (4.00), 2.323 (0.63), 2.328 (0.70), 2.366 (0.42), 2.524(1.74), 2.670 (0.54), 3.494 (4.95), 4.350 (0.61), 4.371 (1.07), 4.392(1.03), 4.412 (0.56), 5.754 (1.16), 7.126 (3.15), 7.149 (3.22), 7.543(2.11), 7.565 (4.02), 7.587 (2.14), 8.284 (3.99), 8.306 (3.73), 8.811(6.22), 10.498 (2.43), 10.521 (2.35). 491

LC-MS (Method 3): R_(t) = 1.76 min m/z = 545 [M + H]⁺ ¹H-NMR (400 MHz,DMSO-d₆) δ [ppm]: −0.149 (0.45), −0.008 (4.12), 0.008 (3.53), 0.146(0.46), 0.322 (1.80), 0.333 (2.84), 0.346 (2.88), 0.357 (2.23), 0.369(1.13), 0.509 (1.97), 0.520 (2.93), 0.533 (2.58), 0.547 (2.54), 0.555(2.30), 0.567 (2.93), 0.577 (2.52), 0.588 (2.25), 0.598 (1.89), 0.612(1.13), 0.626 (1.39), 0.636 (1.63), 0.646 (2.58), 0.657 (2.36), 0.662(2.26), 0.671 (2.23), 0.682 (1.10), 0.691 (0.72), 1.163 (0.59), 1.175(1.21), 1.183 (1.76), 1.195 (3.01), 1.204 (2.17), 1.216 (3.01), 1.228(1.78), 1.236 (1.60), 2.328 (1.08), 2.366 (0.67), 2.524 (3.51), 2.670(1.28), 2.710 (0.85), 2.832 (1.95), 3.136 (2.77), 3.371 (1.04), 3.488(1.45), 3.690 (0.58), 4.352 (1.52), 4.372 (2.82), 4.394 (3.08), 4.414(2.02), 4.608 (0.82), 4.744 (0.67), 4.937 (0.61), 6.935 (0.85), 7.541(3.01), 8.273 (1.43), 8.793 (16.00), 10.551 (3.17), 10.575 (3.08). 492

LC-MS (Method 3): R_(t) = 2.06 min m/z = 539 [M + H]⁺ ¹H-NMR (400 MHz,DMSO-d₆) δ [ppm]: −0.008 (1.90), 0.008 (1.59), 0.314 (0.60), 0.325(0.95), 0.337 (0.94), 0.348 (0.72), 0.505 (0.67), 0.517 (0.97), 0.530(0.86), 0.541 (0.95), 0.549 (0.73), 0.560 (0.98), 0.571 (0.79), 0.581(0.74), 0.591 (0.60), 0.622 (0.51), 0.632 (0.53), 0.642 (0.86), 0.653(0.77), 0.659 (0.76), 0.666 (0.73), 1.172 (0.40), 1.181 (0.55), 1.193(1.00), 1.201 (0.71), 1.213 (0.98), 1.225 (0.52), 1.233 (0.47), 2.073(7.30), 2.328 (0.46), 2.524 (1.43), 2.670 (0.46), 4.348 (0.62), 4.368(0.92), 4.390 (0.90), 4.410 (0.48), 4.658 (16.00), 5.754 (1.18), 6.593(3.51), 6.615 (3.56), 7.530 (1.77), 7.552 (3.33), 7.574 (1.80), 8.272(3.89), 8.294 (3.66), 8.796 (5.72), 10.506 (1.93), 10.530 (1.84). 493

LC-MS (Method 3): R_(t) = 2.01 min m/z = 529 [M + H]⁺ ¹H-NMR (400 MHz,DMSO-d₆) δ [ppm]: −0.149 (0.59), −0.008 (8.10), 0.008 (5.14), 0.146(0.65), 0.322 (2.70), 0.333 (3.90), 0.345 (3.93), 0.357 (2.97), 0.369(1.47), 0.508 (2.94), 0.520 (4.26), 0.532 (3.73), 0.546 (3.67), 0.554(3.38), 0.566 (4.17), 0.576 (3.61), 0.587 (3.29), 0.597 (2.73), 0.611(1.85), 0.625 (2.23), 0.635 (2.58), 0.646 (3.76), 0.656 (3.58), 0.661(3.46), 0.670 (3.38), 0.678 (1.94), 0.691 (1.73), 0.737 (4.79), 1.076(1.32), 1.163 (1.20), 1.175 (2.03), 1.183 (2.70), 1.195 (4.37), 1.204(3.14), 1.216 (4.23), 1.228 (2.64), 1.236 (2.44), 2.328 (1.41), 2.366(1.14), 2.524 (8.46), 2.670 (1.73), 2.710 (1.32), 2.834 (2.14), 3.142(5.58), 3.420 (2.79), 3.602 (1.32), 3.865 (0.47), 4.354 (2.32), 4.375(3.64), 4.396 (3.29), 4.416 (1.88), 4.631 (1.79), 4.825 (0.50), 5.754(0.53), 6.927 (1.61), 7.546 (5.55), 7.568 (9.95), 7.590 (5.40), 8.281(2.08), 8.804 (16.00), 10.546 (4.40), 10.569 (4.20). 494

LC-MS (Method 3): R_(t) = 2.01 min m/z = 529 [M + H]⁺ ¹H-NMR (400 MHz,DMSO-d₆) δ [ppm]: −0.149 (0.60), −0.008 (5.76), 0.008 (5.76), 0.146(0.70), 0.323 (2.44), 0.334 (3.89), 0.346 (3.91), 0.358 (3.04), 0.369(1.55), 0.510 (2.67), 0.522 (3.96), 0.534 (3.49), 0.547 (3.66), 0.555(3.17), 0.567 (3.99), 0.578 (3.41), 0.588 (3.17), 0.599 (2.59), 0.612(1.67), 0.626 (2.02), 0.637 (2.27), 0.647 (3.64), 0.658 (3.29), 0.663(3.24), 0.671 (3.26), 0.683 (1.82), 0.693 (1.60), 0.742 (4.64), 1.079(1.25), 1.163 (0.90), 1.175 (1.72), 1.183 (2.52), 1.195 (4.06), 1.204(2.99), 1.216 (4.04), 1.228 (2.49), 1.236 (2.12), 1.249 (0.85), 2.073(0.47), 2.328 (1.42), 2.366 (1.05), 2.523 (5.73), 2.670 (1.69), 2.710(1.17), 2.835 (1.99), 3.140 (5.51), 3.420 (2.77), 3.452 (1.87), 3.606(1.25), 3.877 (0.45), 4.330 (0.50), 4.350 (2.02), 4.372 (3.59), 4.392(3.46), 4.413 (1.87), 4.625 (1.72), 4.826 (0.47), 6.925 (1.57), 7.546(5.38), 7.568 (10.14), 7.590 (5.53), 8.281 (1.94), 8.804 (16.00), 10.546(4.54), 10.569 (4.46). 495

LC-MS (Method 1): R_(t) = 1.06 min m/z = 517 [M + H]⁺ ¹H-NMR (400 MHz,DMSO-d₆) δ [ppm]: 0.008 (1.41), 0.744 (2.98), 0.953 (7.32), 0.971(16.00), 0.989 (8.01), 1.072 (0.79), 1.233 (0.48), 1.603 (1.07), 1.621(1.44), 1.628 (1.30), 1.638 (1.76), 1.646 (1.56), 1.656 (1.51), 1.663(1.70), 1.682 (1.28), 1.832 (0.43), 1.851 (1.32), 1.861 (1.53), 1.869(1.55), 1.879 (1.73), 1.886 (1.56), 1.896 (1.35), 1.904 (1.16), 1.914(0.98), 2.672 (0.42), 2.837 (1.27), 3.140 (3.52), 3.423 (1.78), 3.455(1.21), 3.606 (0.79), 4.626 (1.12), 4.732 (1.60), 4.752 (1.51), 6.925(1.01), 7.549 (3.71), 7.571 (7.04), 7.593 (3.75), 8.277 (1.34), 8.814(11.16), 10.413 (2.70), 10.437 (2.70). 496

LC-MS (Method 3): R_(t) = 1.29 min m/z = 528 [M + H]⁺ ¹H-NMR (400 MHz,DMSO-d₆) δ [ppm]: −0.008 (2.46), 0.008 (1.22), 0.949 (3.48), 0.968(7.30), 0.986 (3.51), 1.602 (0.53), 1.620 (0.71), 1.627 (0.64), 1.637(0.86), 1.646 (0.74), 1.655 (0.73), 1.662 (0.79), 1.681 (0.59), 1.850(0.66), 1.859 (0.74), 1.868 (0.76), 1.878 (0.82), 1.884 (0.72), 1.894(0.63), 1.903 (0.55), 1.913 (0.44), 2.074 (2.23), 2.159 (16.00), 2.275(4.12), 2.287 (5.55), 2.299 (3.79), 2.324 (0.52), 2.329 (0.50), 2.520(1.93), 2.524 (1.72), 2.671 (0.41), 3.494 (4.82), 4.732 (0.68), 4.744(0.64), 7.125 (3.28), 7.148 (3.25), 7.546 (2.19), 7.568 (3.87), 7.590(2.11), 8.281 (4.40), 8.303 (4.08), 8.820 (6.90), 10.361 (2.35), 10.385(2.20). 497

LC-MS (Method 1): R_(t) = 1.06 min m/z = 517 [M + H]⁺ ¹H-NMR (400 MHz,DMSO-d₆) δ [ppm]: 0.008 (1.19), 0.741 (2.95), 0.951 (7.33), 0.969(16.00), 0.988 (7.97), 1.075 (0.77), 1.601 (1.08), 1.619 (1.44), 1.626(1.29), 1.636 (1.75), 1.645 (1.57), 1.655 (1.49), 1.662 (1.69), 1.680(1.28), 1.832 (0.43), 1.841 (0.55), 1.850 (1.31), 1.860 (1.52), 1.868(1.53), 1.878 (1.73), 1.885 (1.53), 1.895 (1.33), 1.903 (1.15), 1.913(0.96), 2.524 (1.06), 2.835 (1.25), 3.140 (3.53), 3.422 (1.68), 3.454(1.12), 3.610 (0.78), 4.633 (1.10), 4.677 (0.40), 4.708 (0.94), 4.723(1.49), 4.732 (1.56), 4.752 (1.47), 4.767 (0.90), 6.927 (1.00), 7.550(3.12), 7.571 (5.75), 7.593 (3.15), 8.279 (1.27), 8.815 (9.96), 10.413(2.71), 10.437 (2.67). 498

LC-MS (Method 1): R_(t) = 1.09 min m/z = 527 [M + H]⁺ ¹H-NMR (400 MHz,DMSO-d₆) δ [ppm]: −0.062 (5.60), −0.008 (0.86), 0.945 (2.72), 0.963(6.04), 0.981 (2.96), 1.597 (0.40), 1.615 (0.55), 1.622 (0.49), 1.632(0.65), 1.640 (0.59), 1.650 (0.56), 1.658 (0.65), 1.676 (0.49), 1.846(0.49), 1.855 (0.56), 1.864 (0.58), 1.874 (0.65), 1.880 (0.58), 1.891(0.50), 1.899 (0.43), 2.074 (1.54), 4.660 (16.00), 4.727 (0.57), 4.747(0.55), 6.592 (3.38), 6.614 (3.40), 7.533 (1.68), 7.555 (3.05), 7.577(1.68), 8.269 (3.76), 8.291 (3.59), 8.806 (5.71), 10.371 (1.89), 10.395(1.83). 499

LC-MS (Method 3): R_(t) = 2.30 min m/z 501 [M + H]⁺ ¹H-NMR (400 MHz,DMSO-d₆) δ [ppm]: 0.947 (1.18), 0.966 (2.54), 0.984 (1.25), 1.101(16.00), 5.756 (1.58), 6.696 (1.28), 6.718 (1.30), 7.564 (0.71), 7.586(1.32), 7.608 (0.71), 7.706 (1.31), 8.099 (1.42), 8.121 (1.33), 8.793(2.57), 10.463 (0.78), 10.487 (0.76). 500

LC-MS (Method 3): R_(t) = 1.79 min m/z 573 [M + H]⁺ ¹H-NMR (400 MHz,DMSO-d₆) δ [ppm]: −0.149 (0.46), 0.008 (4.07), 0.146 (0.50), 0.949(6.73), 0.967 (14.80), 0.986 (7.36), 1.236 (0.98), 1.334 (5.59), 1.600(1.00), 1.618 (1.26), 1.635 (1.55), 1.643 (1.41), 1.660 (1.55), 1.679(1.26), 1.849 (1.11), 1.858 (1.35), 1.867 (1.39), 1.877 (1.61), 1.894(1.22), 1.912 (0.94), 2.328 (1.37), 2.366 (0.87), 2.670 (1.39), 2.710(0.91), 3.276 (15.39), 3.290 (16.00), 3.471 (5.03), 4.291 (1.07), 4.399(5.14), 4.412 (11.69), 4.425 (4.99), 4.724 (1.35), 4.811 (0.44), 5.754(1.89), 7.076 (5.44), 7.099 (5.70), 7.127 (0.54), 7.544 (4.24), 7.566(7.79), 7.588 (4.11), 8.241 (7.03), 8.263 (6.70), 8.291 (0.57), 8.801(12.73), 8.815 (1.11), 10.404 (4.64), 10.428 (4.22). 501

LC-MS (Method 3): R_(t) = 2.19 min m/z 503 [M + H]⁺ ¹H-NMR (400 MHz,DMSO-d₆) δ [ppm]: −0.149 (0.53), 0.147 (0.78), 0.949 (7.00), 0.968(16.00), 0.986 (7.76), 1.235 (3.76), 1.398 (2.13), 1.603 (1.09), 1.621(1.51), 1.639 (1.71), 1.663 (1.60), 1.681 (1.22), 1.868 (1.53), 1.879(1.71), 1.895 (1.38), 2.073 (0.87), 2.328 (1.18), 2.367 (0.71), 2.670(1.42), 2.711 (0.73), 3.997 (1.27), 4.276 (1.38), 4.747 (1.51), 5.378(1.67), 5.522 (1.69), 6.671 (8.96), 6.693 (8.89), 7.524 (4.58), 7.546(8.47), 7.568 (4.60), 8.318 (9.71), 8.340 (9.11), 8.834 (14.82), 10.344(4.87), 10.369 (4.64).

Example 5027-[3,3-Bis(hydroxymethyl)azetidin-1-yl]-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

The compound from Example 492 (86.0 mg, 160 μmol) was initially chargedin 1 ml of trifluoroacetic acid, 1 ml of water and 1 ml of acetonitrilewere added, and the mixture was stirred at room temperature over theweekend. The mixture was purified by means of preparative HPLC (RP18column, eluent: acetonitrile/water gradient with addition of 0.1% TFA).The product fractions were very substantially concentrated by rotaryevaporation; the residue was extracted twice with dichloromethane. Thecombined organic phases were washed twice with saturated aqueous sodiumhydrogencarbonate solution. The combined aqueous phases werere-extracted once with dichloromethane. The combined organic phases weredried over sodium sulphate, filtered and concentrated by rotaryevaporation. 86 mg of the target compound (97% of theory) were obtained.

LC-MS (Method 3): R_(t)=1.75 min; MS (ESIpos): m/z=557 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: −0.008 (2.85), 0.008 (2.81), 0.319(1.20), 0.330 (1.93), 0.342 (1.91), 0.354 (1.47), 0.366 (0.73), 0.495(0.49), 0.507 (1.35), 0.518 (1.98), 0.531 (1.75), 0.544 (1.78), 0.553(1.55), 0.564 (1.94), 0.575 (1.69), 0.585 (1.52), 0.596 (1.25), 0.609(0.79), 0.623 (0.98), 0.634 (1.10), 0.645 (1.77), 0.655 (1.61), 0.660(1.54), 0.668 (1.55), 0.676 (0.78), 0.689 (0.54), 0.835 (0.50), 0.853(0.53), 1.161 (0.74), 1.173 (1.24), 1.182 (1.63), 1.194 (2.31), 1.202(1.75), 1.214 (2.20), 1.226 (1.46), 1.234 (1.53), 2.074 (1.23), 2.328(0.58), 2.367 (0.46), 2.671 (0.59), 2.710 (0.43), 3.471 (16.00), 3.484(15.15), 3.820 (2.70), 4.349 (0.99), 4.370 (1.73), 4.391 (1.70), 4.412(0.88), 4.823 (4.75), 4.836 (11.08), 4.850 (4.63), 5.754 (0.48), 6.588(6.33), 6.610 (6.39), 7.519 (3.46), 7.541 (6.53), 7.564 (3.44), 8.246(6.51), 8.268 (6.21), 8.777 (10.05), 10.542 (4.05), 10.565 (3.86).

Example 5037-[3,3-Bis(hydroxymethyl)azetidin-1-yl]-4-oxo-N-[(2S)-trifluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

The compound from Example 498 (80.0 mg, 150 μmol) was initially chargedin 0.94 ml of trifluoroacetic acid, 0.94 ml of water and 0.94 ml ofacetonitrile were added, and the mixture was stirred at room temperaturefor 2 days. The reaction mixture was concentrated and purified by meansof preparative HPLC (RP18 column, mobile phase: acetonitrile/watergradient with addition of 0.1% TFA). The product fractions were verysubstantially concentrated by rotary evaporation; the residue wasextracted twice with dichloromethane. The combined organic phases werewashed twice with saturated aqueous sodium hydrogencarbonate solution.The combined aqueous phases were re-extracted once with dichloromethane.The combined organic phases were dried over sodium sulphate, filteredand concentrated by evaporation. 63 mg of the target compound (76% oftheory) were obtained.

LC-MS (Method 3): R_(t)=1.72 min; MS (ESIpos): m/z=545 [M+H]⁺

Example 5047-[(4S)-4-Hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2S)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

The compound from Example 117A (35.0 mg, 83.5 μmol) was initiallycharged in 1.0 ml of dimethylformamide, and HATU (38.1 mg, 100 μmol) andN,N-diisopropylethylamine (44 μl, 250 μmol) were added. The reactionmixture was stirred at RT for 10 min, and(2S)-1,1,1-trifluoro-3,3-dimethylbutan-2-amine (19.4 mg, 125 μmol)dissolved in 1.0 ml of dimethylformamide was added. The mixture wasstirred for a further 10 min, diluted with acetonitrile/water, filteredthrough a syringe filter and purified by means of preparative RP-HPLC(column: Reprosil 125×30; 10p, flow rate 50 ml/min, MeCN/water/0.1%TFA). The volatile constituents were removed under reduced pressure andthe residue was dried under high vacuum. This gave 40.5 mg (100% purity,87% of theory) of the title compound.

LC-MS (Method 3): R_(t)=2.04 min; MS (ESIpos): m/z=557 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.102 (16.00), 2.359 (0.89), 2.403(1.04), 2.921 (0.87), 2.936 (0.91), 2.964 (0.80), 2.979 (0.79), 3.465(1.13), 3.495 (1.20), 3.677 (0.80), 3.689 (0.97), 3.707 (0.75), 3.719(0.65), 4.296 (0.86), 4.652 (0.73), 7.604 (0.76), 7.613 (0.92), 7.627(0.92), 7.636 (0.77), 8.535 (2.24), 8.557 (2.68), 8.738 (2.64), 8.760(2.19), 9.086 (3.22), 10.465 (1.20), 10.490 (1.15).

Example 505N-[1-Cyclobutyl-2,2,2-trifluoroethyl]-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

The compound from Example 117A (40.0 mg, 95.4 μmol) was initiallycharged in 1.0 ml of dimethylformamide, and HATU (43.5 mg, 114 μmol) andN,N-diisopropylethylamine (49.5 μl, 295 μmol) were added. The reactionmixture was stirred at RT for 10 min, andrac-1-cyclobutyl-2,2,2-trifluoroethanamine hydrochloride (27.1 mg, 143μmol) dissolved in 1.0 ml of dimethylformamide andN,N-diisopropylethylamine (16.5 μl, 95 μmol) was added. The mixture wasstirred for a further 10 min, diluted with acetonitrile/water, filteredthrough a syringe filter and purified by means of preparative RP-HPLC(column: Reprosil 125×30; 10, flow rate 50 ml/min, MeCN/water/0.1% TFA).The volatile constituents were removed under reduced pressure and theresidue was dried under high vacuum. This gave 42.0 mg (100% purity, 79%of theory) of the title compound.

LC-MS (Method 3): R_(t)=2.04 min; MS (ESIpos): m/z=555 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: −0.008 (3.58), 0.008 (3.53), 1.762(2.39), 1.789 (0.95), 1.883 (1.62), 1.891 (1.42), 1.904 (3.54), 1.916(4.79), 1.926 (6.49), 1.933 (5.05), 1.940 (5.04), 1.960 (3.53), 1.990(3.65), 2.005 (4.84), 2.019 (3.84), 2.040 (1.04), 2.074 (0.76), 2.358(4.51), 2.402 (5.27), 2.814 (1.33), 2.834 (2.24), 2.857 (1.87), 2.876(1.04), 2.919 (3.64), 2.933 (3.83), 2.962 (3.27), 2.977 (3.23), 3.467(4.50), 3.496 (5.56), 3.676 (3.62), 3.688 (4.30), 3.706 (3.25), 3.718(2.96), 4.297 (3.95), 4.787 (1.50), 4.806 (2.49), 4.829 (2.58), 4.849(1.47), 5.337 (2.09), 7.597 (2.46), 7.604 (3.04), 7.617 (4.69), 7.626(4.84), 7.634 (2.83), 7.640 (2.96), 7.647 (2.43), 8.536 (11.34), 8.559(13.70), 8.728 (13.13), 8.750 (10.68), 9.090 (16.00), 10.272 (5.16),10.296 (4.99).

25.8 mg of the title compound (diastereomer mixture) were separated intothe diastereomers by chiral HPLC (preparative HPLC: column: DaicelChiralpak IE-H 5 m 250×25 mm; eluent: 15% ethanol, 75% n-heptane; flowrate: 20 ml/min; UV detection: 220 nm).

This gave (in the sequence of elution from the column) 8 mg ofdiastereomer 1 from Example 506 (99% de) R_(t)=7.20 min and 15 mg (99%de) of diastereomer 2 from Example 507 R_(t)=8.83 min.

[Analytical HPLC: column: Chiralpak IE-3 5 m 250×4.6 mm; eluent: 25%ethanol, 75% isohexane; temperature: 30° C.; flow rate: 1.0 ml/min; UVdetection: 220 nm]

Example 506N-[1-Cyclobutyl-2,2,2-trifluoroethyl]-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

LC-MS (Method 3): R_(t)=2.03 min; MS (ESIpos): m/z=555 [M+H]⁺

Example 507N-[1-Cyclobutyl-2,2,2-trifluoroethyl]-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2)

LC-MS (Method 3): R_(t)=2.02 min; MS (ESIpos): m/z=555 [M+H]⁺

Example 508N-[2-Cyclopropyl-1,1,1-trifluoropropan-2-yl]-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

The compound from Example 117A (35.0 mg, 83.5 μmol) was initiallycharged in 1.0 ml of dimethylformamide, and HATU (38.1 mg, 100 μmol) andN,N-diisopropylethylamine (44 μl, 250 μmol) were added. The reactionmixture was stirred at RT for 10 min, andrac-2-cyclopropyl-1,1,1-trifluoropropan-2-amine hydrochloride (23.7 mg,125 μmol) dissolved in 1.0 ml of dimethylformamide andN,N-diisopropylethylamine (15 μl, 83.5 μmol) was added. The mixture wasstirred for a further 10 min, diluted with acetonitrile/water, filteredthrough a syringe filter and purified by means of preparative RP-HPLC(column: Reprosil 125×30; 10μ, flow rate 50 ml/min, MeCN/water/0.1%TFA). The volatile constituents were removed under reduced pressure andthe residue was dried under high vacuum. This gave 31.1 mg (100% purity,67% of theory) of the title compound.

LC-MS (Method 3): R_(t)=1.98 min; MS (ESIpos): m/z=555 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: −0.149 (0.61), −0.008 (5.62), 0.008(4.93), 0.146 (0.60), 0.512 (1.29), 0.576 (3.31), 0.597 (3.28), 0.696(1.33), 1.415 (0.99), 1.422 (0.99), 1.432 (1.47), 1.435 (1.43), 1.444(1.03), 1.609 (16.00), 2.355 (2.29), 2.398 (2.68), 2.914 (2.19), 2.929(2.31), 2.957 (2.01), 2.972 (1.93), 3.460 (2.44), 3.490 (2.91), 3.670(2.01), 3.682 (2.46), 3.700 (1.89), 3.712 (1.65), 4.279 (1.30), 4.292(2.20), 7.592 (1.30), 7.599 (1.69), 7.611 (2.45), 7.621 (2.55), 7.634(1.67), 7.642 (1.30), 8.521 (5.65), 8.543 (6.72), 8.717 (6.71), 8.739(5.41), 8.999 (9.09), 10.088 (6.29).

30 mg of the title compound (diastereomer mixture) were separated intothe diastereomers by chiral HPLC (preparative HPLC: column: Daicel IB 5m 250×30 mm; eluent: 20% ethanol, 70% n-heptane; flow rate: 20 ml/min;UV detection: 220 nm).

This gave (in the sequence of elution from the column) 2.8 mg ofdiastereomer 1 from Example 509 (99% de) R_(t)=1.58 min and 3.7 mg (99%de) of diastereomer 2 from Example 510 R_(t)=2.86 min.

[Analytical HPLC: column: Chiralpak IB-3 3 m 250×4.6 mm; eluent: 20%ethanol, 80% n-heptane; temperature: 30° C.; flow rate: 1.0 ml/min; UVdetection: 220 nm]

Example 509N-[2-Cyclopropyl-1,1,1-trifluoropropan-2-yl]-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

LC-MS (Method 3): R_(t)=1.99 min; MS (ESIpos): m/z=555 [M+H]⁺

Example 510N-[2-Cyclopropyl-1,1,1-trifluoropropan-2-yl]-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2)

LC-MS (Method 3): R_(t)=2.00 min; MS (ESIpos): m/z=555 [M+H]⁺

Example 5117-[(4S)-4-Hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-(4,4,4-trifluoro-2-methylbutan-2-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

The compound from Example 117A (120 mg, 286 μmol) was initially chargedin 4.0 ml of dimethylformamide, and HATU (131 mg, 343 μmol) andN,N-diisopropylethylamine (150 μl, 870 μmol) were added. The reactionmixture was stirred at RT for 10 min, and4,4,4-trifluoro-2-methylbutan-2-amine hydrochloride (1:1) (76.2 mg, 429μmol) dissolved in 1.0 ml of dimethylformamide andN,N-diisopropylethylamine (50 μl, 290 μmol) was added. The mixture wasstirred for a further 10 min, diluted with acetonitrile/water, filteredthrough a syringe filter and purified by means of preparative RP-HPLC(column: Reprosil 125×30; 10μ, flow rate 50 ml/min, MeCN/water/0.1%TFA). The volatile constituents were removed under reduced pressure andthe residue was dried under high vacuum. This gave 84.4 mg (100% pure,54% of theory) of the title compound.

LC-MS (Method 3): R_(t)=1.89 min; MS (ESIpos): m/z=543 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: −0.008 (0.78), 1.500 (16.00), 2.351(1.25), 2.395 (1.44), 2.912 (1.44), 2.918 (0.93), 2.927 (1.42), 2.948(2.18), 2.955 (1.57), 2.970 (1.54), 2.978 (2.05), 3.007 (0.63), 3.459(1.24), 3.489 (1.53), 3.669 (1.11), 3.681 (1.35), 3.699 (1.04), 3.711(0.90), 4.290 (0.98), 5.325 (0.99), 7.589 (0.69), 7.596 (0.88), 7.609(1.31), 7.619 (1.31), 7.627 (0.77), 7.632 (0.86), 7.639 (0.68), 8.510(3.14), 8.533 (3.85), 8.686 (3.77), 8.708 (2.99), 8.963 (4.50), 9.902(3.32).

Example 512N-[1-Cyclopropyl-3,3,3-trifluoropropyl]-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

The compound from Example 117A (45.0 mg, 107 μmol) was initially chargedin 1.0 ml of dimethylformamide, and HATU (38.1 mg, 100 μmol) andN,N-diisopropylethylamine (57 μl, 321 μmol) were added. The reactionmixture was stirred at RT for 10 min, andrac-1-cyclopropyl-3,3,3-trifluoropropan-1-amine hydrochloride (30.5 mg,161 μmol) dissolved in 1.0 ml of dimethylformamide andN,N-diisopropylethylamine (19 μl, 107 μmol) was added. The mixture wasstirred for a further 10 min, diluted with acetonitrile/water, filteredthrough a syringe filter and purified by means of preparative RP-HPLC(column: Reprosil 125×30; 10μ, flow rate 50 ml/min, MeCN/water/0.1%TFA). The volatile constituents were removed under reduced pressure andthe residue was dried under high vacuum. This gave 45.1 mg (100% purity,76% of theory) of the title compound.

LC-MS (Method 3): R_(t)=1.85 min; MS (ESIpos): m/z=555 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.008 (2.32), 0.295 (1.35), 0.304(2.35), 0.316 (3.52), 0.327 (3.43), 0.346 (3.20), 0.359 (3.36), 0.370(2.17), 0.381 (1.35), 0.457 (1.08), 0.466 (2.14), 0.478 (2.89), 0.488(2.87), 0.498 (2.48), 0.507 (2.64), 0.515 (2.35), 0.528 (3.32), 0.536(2.78), 0.549 (2.23), 0.557 (1.06), 1.150 (1.06), 1.159 (1.62), 1.170(2.69), 1.179 (2.12), 1.191 (2.60), 1.203 (1.40), 1.211 (0.93), 2.329(0.79), 2.352 (4.49), 2.367 (1.13), 2.395 (5.21), 2.520 (3.20), 2.524(2.93), 2.636 (1.02), 2.648 (1.42), 2.666 (1.65), 2.675 (2.84), 2.687(1.78), 2.704 (1.87), 2.711 (1.76), 2.715 (1.67), 2.769 (1.58), 2.789(1.81), 2.798 (1.92), 2.807 (1.26), 2.818 (1.78), 2.828 (1.53), 2.836(1.08), 2.856 (0.99), 2.913 (3.95), 2.928 (4.08), 2.956 (3.59), 2.971(3.50), 3.462 (5.84), 3.492 (7.00), 3.672 (4.08), 3.684 (4.85), 3.701(3.77), 3.714 (3.29), 3.770 (0.95), 3.783 (1.15), 3.792 (2.53), 3.803(2.57), 3.813 (2.55), 3.825 (2.35), 3.834 (1.04), 3.846 (0.81), 4.279(2.60), 4.292 (4.36), 4.305 (2.41), 6.947 (1.38), 7.074 (1.47), 7.202(1.33), 7.586 (2.53), 7.593 (3.14), 7.606 (4.74), 7.616 (4.74), 7.629(3.11), 7.636 (2.41), 8.515 (9.59), 8.537 (11.96), 8.689 (12.12), 8.711(9.66), 8.970 (16.00), 9.869 (6.05), 9.890 (5.84).

40 mg of the title compound (diastereomer mixture) were separated intothe diastereomers by chiral HPLC (preparative HPLC: column: DaicelChiralpak IE-H 5 μm 250×20 mm; eluent: 50% ethanol, 50% n-heptane;temperature: 25° C.; flow rate: 15 ml/min; UV detection: 210 nm).

This gave (in the sequence of elution from the column) 13.2 mg ofdiastereomer 1 (99% de) R_(t)=2.50 min and 13.3 mg (95% de) ofdiastereomer 2 R_(t)=2.91 min.

[Analytical HPLC: column: Chiraltek IE-3 3 μm 250×4.6 mm; eluent: 25%ethanol, 75% isohexane; temperature: 30° C.; flow rate: 1.0 ml/min; UVdetection: 220 nm]

Example 513N-[1-Cyclopropyl-3,3,3-trifluoropropyl]-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

LC-MS (Method 3): R_(t)=1.84 min; MS (ESIpos): m/z=555 [M+H]⁺

Example 514N-[1-Cyclopropyl-3,3,3-trifluoropropyl]-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2)

LC-MS (Method 3): R_(t)=1.84 min; MS (ESIpos): m/z=555 [M+H]⁺

Example 5157-[(4S)-4-Hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[1-(trifluoromethyl)cyclobutyl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

The compound from Example 117A (35.0 mg, 83.5 μmol) was initiallycharged in 1.0 ml of dimethylformamide, and HATU (38.1 mg, 100 μmol) andN,N-diisopropylethylamine (44.0 μl, 246 μmol) were added. The reactionmixture was stirred at RT for 10 min, and1-(trifluoromethyl)cyclobutanamine hydrochloride (22.0 mg, 125 μmol)dissolved in 1.0 ml of dimethylformamide and N,N-diisopropylethylamine(15 μl, 84 μmol) was added. The mixture was stirred for a further 10min, diluted with acetonitrile/water, filtered through a syringe filterand purified by means of preparative RP-HPLC (column: Reprosil 125×30;10p, flow rate 50 ml/min, MeCN/water/0.1% TFA). The volatileconstituents were removed under reduced pressure and the residue wasdried under high vacuum. This gave 35.8 mg (100% pure, 79% of theory) ofthe title compound.

LC-MS (Method 3): R_(t)=1.89 min; MS (ESIpos): m/z=541 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.943 (2.33), 1.964 (2.95), 1.985(2.04), 2.038 (2.61), 2.051 (2.53), 2.073 (5.69), 2.355 (4.96), 2.398(5.89), 2.561 (6.85), 2.576 (7.95), 2.599 (6.71), 2.622 (4.45), 2.914(4.08), 2.929 (4.26), 2.958 (3.72), 2.972 (3.66), 3.462 (5.03), 3.491(6.09), 3.672 (3.95), 3.684 (4.67), 3.702 (3.59), 3.713 (3.21), 4.293(4.61), 5.335 (4.12), 7.615 (6.03), 8.527 (8.73), 8.549 (10.88), 8.700(10.72), 8.723 (8.55), 9.016 (16.00), 10.219 (12.50).

Example 516N-(1,1-Difluoro-2-methylpropan-2-yl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

The compound from Example 117A (40.0 mg, 95.4 μmol) was initiallycharged in 1.0 ml of dimethylformamide, and HATU (43.5 mg, 114 μmol) andN,N-diisopropylethylamine (49.5 μl, 285 μmol) were added. The reactionmixture was stirred at RT for 10 min, and1,1-difluoro-2-methylpropan-2-amine hydrochloride (20.8 mg, 143 μmol)dissolved in 1.0 ml of dimethylformamide and N,N-diisopropylethylamine(16.5 μl, 95 μmol) was added. The mixture was stirred for a further 10min, diluted with acetonitrile/water, filtered through a syringe filterand purified by means of preparative RP-HPLC (column: Reprosil 125×30;10p, flow rate 50 ml/min, MeCN/water/0.1% TFA). The volatileconstituents were removed under reduced pressure and the residue wasdried under high vacuum. This gave 46.4 mg (100% purity, 95% of theory)of the title compound.

LC-MS (Method 3): R_(t)=1.82 min; MS (ESIpos): m/z=511 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.455 (16.00), 2.074 (9.78), 2.353(1.20), 2.396 (1.40), 2.911 (1.02), 2.926 (1.06), 2.955 (0.93), 2.970(0.91), 3.459 (1.18), 3.489 (1.46), 3.669 (0.98), 3.681 (1.16), 3.699(0.89), 3.711 (0.80), 4.292 (1.02), 5.325 (1.11), 5.332 (1.09), 6.289(0.85), 6.432 (1.58), 6.574 (0.73), 7.591 (0.69), 7.599 (0.86), 7.611(1.32), 7.621 (1.33), 7.634 (0.86), 7.641 (0.69), 8.517 (2.07), 8.539(2.63), 8.693 (2.51), 8.715 (2.03), 8.986 (3.49), 10.038 (2.99).

Example 5177-[(4S)-4-Acetamido-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

To an initial charge of Example 151C (25.7 mg, 34.0 μmol) in 2.0 ml ofdichloromethane was added triethylamine (14 μl, 100 μmol). Acetylchloride (2.9 μl, 41 μmol) was added slowly to the reaction mixture at0° C., and then the reaction mixture was stirred at RT overnight. Thevolatile constituents were removed under reduced pressure and theresidue was diluted with acetonitrile/water and purified by means ofpreparative RP-HPLC (column: Reprosil 125×30; 10p, flow rate: 50 ml/min,MeCN/water/0.1% TFA). The volatile constituents were removed underreduced pressure and the residue was dried under high vacuum. This gave16.6 mg (100% purity, 86% of theory) of the title compound.

LC-MS (Method 3): R_(t)=1.77 min; MS (ESIpos): m/z=570 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.964 (3.36), 0.982 (6.75), 1.000(3.60), 1.633 (0.51), 1.655 (0.80), 1.667 (0.95), 1.691 (0.94), 1.710(0.66), 1.776 (16.00), 1.876 (0.94), 1.885 (0.96), 1.895 (1.03), 1.911(0.83), 2.404 (1.58), 2.453 (2.17), 2.969 (1.38), 2.988 (1.50), 3.012(1.28), 3.032 (1.25), 3.437 (1.58), 3.463 (1.75), 3.777 (1.40), 3.793(1.73), 3.806 (1.45), 3.823 (1.29), 4.274 (2.02), 4.765 (1.03), 4.776(1.01), 7.582 (1.88), 7.603 (3.43), 7.625 (1.86), 8.328 (2.08), 8.344(2.05), 8.510 (2.75), 8.532 (3.34), 8.723 (3.32), 8.745 (2.77), 9.073(4.94), 10.091 (2.30), 10.115 (2.24).

Example 5187-[4-(Acetamidomethyl)-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

Potassium carbonate (12.9 mg, 93.6 μmol), palladium(II) acetate (2.80mg, 12.5 μmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (7.22mg, 12.5 μmol) were stirred in 3.0 ml of dioxane under argon at RT for10 minutes. Then the compound from 115A (29.0 mg, 62.4 μmol) and thecompound from Example 152A (11.7 mg) were added and the mixture wasstirred at 80° C. for 4 h. The mixture was purified directly bypreparative RP-HPLC (column: Reprosil 125×30; 10p, flow rate: 50 ml/min,MeCN/water, 0.1% TFA). The volatile constituents were removed underreduced pressure and the residue was dried under high vacuum. This gave1.70 mg (100% purity, 5% of theory) of the title compound.

LC-MS (Method 1): R_(t)=0.97 min; MS (ESIpos): m/z=584 [M+H]⁺

Example 5197-[(4S)-4-Hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[1,1,1,2,2-pentafluoropentan-3-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP1, 1.18 g (2.81 mmol) of the compound from Example 117Awere reacted with 300 mg (1.40 mmol) of the compound from Example 153Bin the presence of 1.28 g (3.37 mmol) of HATU and 2.0 ml (11.0 mmol) ofDIPEA in 8.0 ml of DMF. The crude product was purified by means ofpreparative HPLC (acetonitrile/water/0.1% formic acid). 528 mg (33% oftheory, 100% purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=2.00 min; MS (ESIpos): m/z=579 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.16 (d, 1H), 9.08 (s, 1H), 8.72 (d,1H), 8.54 (d, 1H), 7.56-7.67 (m, 2H), 5.33 (d, 1H), 4.82-4.96 (m, 1H),4.27-4.32 (m, 1H), 3.69 (dd, 1H), 3.48 (d, 1H), 2.95 (dd, 1H), 2.38 (d,1H), 1.88-1.99 (m, 1H), 1.62-1.74 (m, 1H), 0.97 (t, 3H).

523 mg of the title compound (diastereomer mixture) were separated intothe diastereomers by chiral HPLC (preparative HPLC: column: DaicelChiralpak IE 5 m 250×20 mm; eluent: 80% n-heptane, 20% isopropanol;temperature: 30° C.; flow rate: 15 ml/min; UV detection: 220 nm).

This gave (in the sequence of elution from the column) 249 mg (15% oftheory, 100% purity) of diastereomer 1 from Example 520 (99% de)Rt=11.07 min and 241 mg (15% of theory, 100% purity) of diastereomer 2from Example 521 (99% de) Rt=13.85 min.

[Analytical HPLC: column: Daicel Chiralpak IE 5 m 250×4.6 mm; eluent:80% isohexane, 20% isopropanol; temperature: 30° C.; flow rate: 1.0ml/min; UV detection: 220 nm]

Example 5207-[(4S)-4-Hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[1,1,1,2,2-pentafluoropentan-3-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

LC-MS (Method 1): R_(t)=1.08 min; MS (ESIpos): m/z=579 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.16 (d, 1H), 9.08 (s, 1H), 8.72 (d,1H), 8.54 (d, 1H), 7.56-7.67 (m, 2H), 5.34 (d, 1H), 4.82-4.95 (m, 1H),4.27-4.32 (m, 1H), 3.69 (dd, 1H), 3.48 (d, 1H), 2.95 (dd, 1H), 2.38 (d,1H), 1.88-1.98 (m, 1H), 1.62-1.64 (m, 1H), 0.97 (t, 3H).

Example 5217-[(4S)-4-Hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[1,1,1,2,2-pentafluoropentan-3-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2)

LC-MS (Method 1): R_(t)=1.08 min; MS (ESIpos): m/z=579 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.16 (d, 1H), 9.08 (s, 1H), 8.72 (d,1H), 8.54 (d, 1H), 7.57-7.67 (m, 2H), 5.33 (d, 1H), 4.82-4.96 (m, 1H),4.27-4.32 (m, 1H), 3.69 (dd, 1H), 3.47 (d, 1H), 2.95 (dd, 1H), 2.38 (d,1H), 1.88-1.99 (m, 1H), 1.62-1.74 (m, 1H), 0.98 (t, 3H).

Example 5227-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-4-oxo-N-[1,1,1,2,2-pentauoropentan-3-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP1, 947 mg (2.25 mmol) of the compound from Example 121Awere reacted with 300 mg (1.40 mmol) of the compound from Example 153Bin the presence of 1.03 g (2.70 mmol) of HATU and 1.6 ml (9.00 mmol) ofDIPEA in 6.4 ml of DMF. The crude product was purified by means ofpreparative HPLC (acetonitrile/water/0.1% formic acid). 477 mg (37% oftheory, 100% purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.83 min; MS (ESIpos): m/z=581 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.48 (d, 1H), 8.81 (s, 1H), 8.28 (d,1H), 7.53-7.60 (m, 2H), 6.78 (d, 1H), 5.24 (d, 1H), 5.14 (d, 1H),4.80-4.93 (m, 1H), 4.03-4.07 (m, 1H), 3.90-3.95 (m, 1H), 3.58-3.64 (m,1H), 3.32-3.37 (m, 1H), 3.21-3.30 (m, 1H), 3.03-3.10 (m, 1H), 1.86-1.97(m, 1H), 1.60-1.72 (m, 1H), 0.96 (t, 3H).

472 mg of the title compound (diastereomer mixture) were separated intothe diastereomers by chiral HPLC (preparative HPLC: column: DaicelChiralpak IA 5 μm 250×15 mm; eluent: 85% n-heptane, 20% isopropanol;temperature: 30° C.; flow rate: 15 ml/min; UV detection: 220 nm).

This gave (in the sequence of elution from the column) 203 mg (16% oftheory, 100% purity) of diastereomer 1 from Example 523 (99% de)Rt=12.94 min and 209 mg (16% of theory, 100% purity) of diastereomer 2from Example 524 (99% de) Rt=15.48 min.

[Analytical HPLC: column: Daicel Chiralpak IA 5 μm 250×4.6 mm; eluent:80% isohexane, 20% isopropanol; temperature: 25° C.; flow rate: 1.0ml/min; UV detection: 220 nm]

Example 5237-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-4-oxo-N-[1,1,1,2,2-pentafluoropentan-3-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

LC-MS (Method 3): R_(t)=1.83 min; MS (ESIpos): m/z=581 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.48 (d, 1H), 8.81 (s, 1H), 8.28 (d,1H), 7.53-7.60 (m, 2H), 6.78 (d, 1H), 5.23 (d, 1H), 5.14 (d, 1H),4.80-4.93 (m, 1H), 4.05 (br s, 1H), 3.93 (br s, 1H), 3.62 (dd, 1H),3.32-3.37 (m, 1H), 3.25 (dd, 1H), 3.07 (d, 1H), 1.87-1.97 (m, 1H),1.60-1.71 (m, 1H), 0.96 (t, 3H).

Example 5247-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-4-oxo-N-[1,1,1,2,2-pentafluoropentan-3-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2)

LC-MS (Method 3): R_(t)=1.83 min; MS (ESIpos): m/z=581 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.48 (d, 1H), 8.81 (s, 1H), 8.28 (d,1H), 7.52-7.60 (m, 2H), 6.78 (d, 1H), 5.24 (d, 1H), 5.14 (d, 1H),4.79-4.93 (m, 1H), 4.05 (br s, 1H), 3.93 (br s, 1H), 3.61 (br dd, 1H),3.32-3.37 (m, 1H), 3.20-3.29 (m, 1H), 3.07 (br d, 1H), 1.86-1.97 (m,1H), 1.59-1.72 (m, 1H), 0.96 (t, 3H).

Example 5257-[(4S)-4-Hydroxy-2-oxopyrrolidin-1-yl]-oxo-N-[(2S)-1,1,1-trifluoro-4-methylpentan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 50.0 mg (119 μmol) of the compound from Example 117Awere reacted with 27.4 mg (143 μmol) of(2R)-1,1,1-trifluoro-4-methylpentan-2-amine hydrochloride in thepresence of 54.4 mg (143 μmol) of HATU and 62 μl (360 μmol) of DIPEA in460 μl of DMF. The crude product was purified by means of preparativeHPLC (acetonitrile/water/0.1% formic acid). 50.3 mg (76% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=2.10 min; MS (ESIpos): m/z=557 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.10 (d, 1H), 9.07 (s, 1H), 8.71 (d,1H), 8.54 (d, 1H), 7.58-7.66 (m, 2H), 5.33 (d, 1H), 4.80-4.90 (m, 1H),4.27-4.31 (m, 1H), 3.69 (dd, 1H), 3.47 (d, 1H), 2.94 (dd, 1H), 2.38 (d,1H), 1.64-1.75 (m, 2H), 1.54-1.62 (m, 1H), 0.95 (d, 3H), 0.90 (d, 3H).

Example 5267-[(4S)-4-Hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[1,1,1-trifluoro-3-methylbutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP1, 80.0 mg (191 μmol) of the compound from Example 117Awere reacted with 32.3 mg (229 μmol) of1,1,1-trifluoro-3-methylbutan-2-amine in the presence of 87.1 mg (229μmol) of HATU and 100 μl (570 μmol) of DIPEA in 1.4 ml of DMF. The crudeproduct was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 81.5 mg (79% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.97 min; MS (ESIpos): m/z=543 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.32 (d, 1H), 9.08 (s, 1H), 8.74 (d,1H), 8.54 (d, 1H), 7.58-7.66 (m, 2H), 5.33 (dd, 1H), 4.74-4.84 (m, 1H),4.27-4.32 (m, 1H), 3.69 (dd, 1H), 3.48 (d, 1H), 2.95 (dd, 1H), 2.38 (d,1H), 2.22-2.31 (m, 1H), 1.04 (d, 3H), 0.98 (d, 3H).

68.0 mg of the title compound (diastereomer mixture) were separated intothe diastereomers by chiral HPLC (preparative HPLC: column: DaicelChiralcel OX-H 5 m 250×20 mm; eluent: 50% n-heptane, 50% isopropanol;temperature: 40° C.; flow rate: 15 ml/min; UV detection: 220 nm).

This gave (in the sequence of elution from the column) 31.0 mg (30% oftheory, 100% purity) of diastereomer 1 from Example 527 (99% de) Rt=4.55min and 31.0 mg (30% of theory, 100% purity) of diastereomer 2 fromExample 528 (99% de) Rt=6.48 min.

[Analytical HPLC: column: Daicel Chiralcel OX-H 5 m 250×4.6 mm; eluent:50% isohexane, 50% isopropanol; temperature: 45° C.; flow rate: 1.0ml/min; UV detection: 220 nm]

Example 5277-[(4S)-4-Hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[1,1,1-trifluoro-3-methylbutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

LC-MS (Method 3): R_(t)=1.94 min; MS (ESIpos): m/z=543 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.32 (d, 1H), 9.08 (s, 1H), 8.74 (d,1H), 8.54 (d, 1H), 7.58-7.66 (m, 2H), 5.34 (d, 1H), 4.74-4.84 (m, 1H),4.27-4.32 (m, 1H), 3.69 (dd, 1H), 3.48 (br d, 1H), 2.95 (dd, 1H), 2.38(br d, 1H), 2.22-2.31 (m, 1H), 1.04 (d, 3H), 0.98 (d, 3H).

Example 5287-[(4S)-4-Hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[1,1,1-trifluoro-3-methylbutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2)

LC-MS (Method 3): R_(t)=1.95 min; MS (ESIpos): m/z=543 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.32 (d, 1H), 9.08 (s, 1H), 8.74 (d,1H), 8.54 (d, 1H), 7.58-7.66 (m, 2H), 5.33 (d, 1H), 4.74-4.84 (m, 1H),4.27-4.32 (m, 1H), 3.70 (dd, 1H), 3.48 (br d, 1H), 2.95 (dd, 1H), 2.38(br d, 1H), 2.22-2.31 (m, 1H), 1.04 (d, 3H), 0.98 (d, 3H).

Example 5297-[(4S)-4-Hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[3,3,4,4,4-pentafluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP1, 500 mg (1.19 mmol) of the compound from Example 117Awere reacted with 262 mg (1.31 mmol) of the compound 147B in thepresence of 544 mg (1.43 mmol) of HATU and 830 μl (4.80 mmol) of DIPEAin 5.0 ml of DMF. The crude product was purified by means of preparativeHPLC (acetonitrile/water/0.1% formic acid). 498 mg (74% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.91 min; MS (ESIpos): m/z=565 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.24 (d, 1H), 9.08 (s, 1H), 8.71 (d,1H), 8.54 (dd, 1H), 7.58-7.65 (m, 2H), 5.33 (t, 1H), 4.97-5.11 (m, 1H),4.27-4.32 (m, 1H), 3.66-3.72 (m, 1H), 3.45-3.50 (m, 1H), 2.94 (ddd, 1H),2.37 (br d, 1H), 1.41 (d, 3H).

492 mg of the title compound (diastereomer mixture) were separated intothe diastereomers by chiral HPLC (preparative HPLC: column: DaicelChiralpak AD-H 5 m 250×20 mm; eluent: 80% n-heptane, 20% isopropanol;temperature: 23° C.; flow rate: 20 ml/min; UV detection: 220 nm).

This gave (in the sequence of elution from the column) 200.4 mg (30% oftheory, 100% purity) of diastereomer 1 from Example 530 (99% de) Rt=6.05min and 199 mg (30% of theory, 100% purity) of diastereomer 2 fromExample 531 (99% de) Rt=8.82 min.

[Analytical HPLC: column: Daicel AD-3 3 m 50×4.6 mm; eluent: 80%isohexane, 20% isopropanol; UV detection: 220 nm].

Example 5307-[(4S)-4-Hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[3,3,4,4,4-pentafluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

LC-MS (Method 3): R_(t)=1.89 min; MS (ESIpos): m/z=565 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.24 (d, 1H), 9.07 (s, 1H), 8.71 (d,1H), 8.54 (d, 1H), 7.54-7.69 (m, 2H), 5.34 (d, 1H), 4.98-5.12 (m, 1H),4.26-4.32 (m, 1H), 3.69 (dd, 1H), 3.48 (br d, 1H), 2.94 (dd, 1H), 2.38(br d, 1H), 1.41 (d, 3H).

Example 5317-[(4S)-4-Hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[3,3,4,4,4-pentafluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2)

LC-MS (Method 3): R_(t)=1.90 min; MS (ESIpos): m/z=565 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.24 (d, 1H), 9.08 (s, 1H), 8.71 (d,1H), 8.54 (d, 1H), 7.58-7.65 (m, 2H), 5.33 (d, 1H), 4.98-5.12 (m, 1H),4.27-4.32 (m, 1H), 3.69 (dd, 1H), 3.47 (br d, 1H), 2.95 (dd, 1H), 2.37(br d, 1H), 1.41 (d, 3H).

Example 532N-[1-(2-Chlorophenyl)-2,2,2-trifluoroethyl]-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP1, 50.0 mg (119 μmol) of7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid were reacted with 30.0 mg (143 μmol) of1-(2-chlorophenyl)-2,2,2-trifluoroethanamine in the presence of 54.4 mg(143 mmol) of HATU and 62 μl (360 μmol) of DIPEA in 460 μl of DMF. Thecrude product was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 41.9 mg (58% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=2.14 min; MS (ESIpos): m/z=611 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=11.21 (d, 1H), 9.09 (s, 1H), 8.76 (d,1H), 8.56 (d, 1H), 7.44-7.70 (m, 6H), 6.42-6.51 (m, 1H), 5.30-5.37 (m,1H), 4.27-4.32 (m, 1H), 3.65-3.72 (m, 1H), 3.42-3.51 (m, 1H), 2.94 (ddd,1H), 2.38 (d, 1H).

35.8 mg of the title compound (diastereomer mixture) were separated intothe diastereomers by chiral HPLC (preparative HPLC: column: YMCChiralart Amylose SA 5 m 250×30 mm; eluent: 60% n-heptane, 40%isopropanol; temperature: 30° C.; flow rate: 30 ml/min; UV detection:220 nm).

This gave (in the sequence of elution from the column) 15.0 mg ofdiastereomer 1 (99% de) Rt=6.50 min and 15.0 mg (99% de) of diastereomer2 Rt=8.62 min.

[Analytical HPLC: column: YMC Chiralart Amylose SA 5 m 250×4.6 mm;eluent: 60% isohexane, 40% isopropanol; temperature: 30° C.; flow rate:1.0 ml/min; UV detection: 220 nm]

Diastereomer 1 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125*40 mm, solvent: acetonitrile,water, 0.1% formic acid), and 13.4 mg (19% of theory, 100% purity) ofthe title compound from Example 533 were obtained.

Diastereomer 2 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125*40 mm, solvent: acetonitrile,water, 0.1% formic acid), and 13.2 mg (18% of theory, 100% purity) ofthe title compound from Example 534 were obtained.

Example 533N-[1-(2-Chlorophenyl)-2,2,2-trifluoroethyl]-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

LC-MS (Method 1): R_(t)=1.13 min; MS (ESIpos): m/z=611 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=11.21 (d, 1H), 9.09 (s, 1H), 8.76 (d,1H), 8.56 (d, 1H), 7.46-7.70 (m, 6H), 6.42-6.51 (m, 1H), 5.33 (d, 1H),4.27-4.32 (m, 1H), 3.69 (dd, 1H), 3.47 (d, 1H), 2.95 (dd, 1H), 2.38 (brd, 1H).

Example 534N-[1-(2-Chlorophenyl)-2,2,2-trifluoroethyl]-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2)

LC-MS (Method 1): R_(t)=1.13 min; MS (ESIpos): m/z=611 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=11.21 (d, 1H), 9.09 (s, 1H), 8.76 (d,1H), 8.56 (d, 1H), 7.48-7.66 (m, 6H), 6.42-6.51 (m, 1H), 5.34 (d, 1H),4.27-4.31 (m, 1H), 3.68 (dd, 1H), 3.47 (br d, 1H), 2.94 (dd, 1H), 2.38(br d, 1H).

Example 535 N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[(3S)-3-methoxypyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP3, 60.0 mg (126 μmol) of the compound from Example 126Awere reacted with 22.6 mg (164 μmol) of (3S)-3-methoxypyrrolidinehydrochloride and 99 μl (570 μmol) of DIPEA in 700 μl of DMF. The crudeproduct was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 58.2 mg (85% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=2.27 min; MS (ESIpos): m/z=541 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.56 (d, 1H), 8.80 (s, 1H), 8.29 (d,1H), 7.51-7.61 (m, 2H), 6.79 (d, 1H), 4.33-4.43 (m, 1H), 3.94-4.11 (m,1H), 3.48-3.60 (m, 1.5H), 3.37-3.47 (m, 0.5H), 3.16-3.28 (m, 4.5H),3.04-3.14 (m, 0.5H), 1.89-2.15 (m, 2H), 1.16-1.25 (m, 1H), 0.50-0.69 (m,3H), 0.31-0.38 (m, 1H).

Example 5364-Oxo-7-(2-oxoimidazolidin-1-yl)-N-[1,1,1-trifluoro-3-methylbutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Racemate)

According to GP1, 80.0 mg (198 μmol) of the compound from Example 113Awere reacted with 33.5 mg (237 μmol) of1,1,1-trifluoro-3-methylbutan-2-amine in the presence of 90.3 mg (237μmol) of HATU and 100 μl (590 μmol) of DIPEA in 1.4 ml of DMF. The crudeproduct was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 68.7 mg (66% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=2.03 min; MS (ESIpos): m/z=528 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.41 (d, 1H), 9.00 (s, 1H), 8.58 (d,1H), 8.44 (d, 1H), 7.67 (s, 1H), 7.58 (t, 2H), 4.73-4.83 (m, 1H),3.55-3.63 (m, 2H), 3.32-3.38 (m, 2H), 2.21-2.30 (m, 1H), 1.04 (d, 3H),0.97 (d, 3H).

57.0 mg of the title compound (racemate) were separated into theenantiomers by chiral HPLC (preparative HPLC: column: Daicel ChiralpakIE 5 μm 250×30 mm; eluent: 70% n-heptane, 20% isopropanol; temperature:23° C.; flow rate: 20 ml/min; UV detection: 257 nm).

This gave (in the sequence of elution from the column) 23.1 mg ofenantiomer 1 (99% de) Rt=14.57 min and 24.4 mg (96% de) of enantiomer 2Rt=18.53 min.

[Analytical HPLC: column: Daicel Chiralpak IF-3 3 μm 50×4.6 mm; eluent:80% n-heptane, 20% isopropanol; temperature: 30° C.; flow rate: 1.0ml/min; UV detection: 255 nm]

Enantiomer 1 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125*40 mm, solvent: acetonitrile,water, 0.1% formic acid), and 11.0 mg (11% of theory, 100% purity) ofthe title compound from Example 537 were obtained.

Enantiomer 2 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125*40 mm, solvent: acetonitrile,water, 0.1% formic acid), and 12.9 mg (12% of theory, 100% purity) ofthe title compound from Example 538 were obtained.

Example 5374-Oxo-7-(2-oxoimidazolidin-1-yl)-N-[1,1,1-trifluoro-3-methylbutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Enantiomer 1)

LC-MS (Method 3): R_(t)=2.01 min; MS (ESIpos): m/z=528 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.42 (d, 1H), 9.00 (s, 1H), 8.59 (d,1H), 8.44 (d, 1H), 7.67 (s, 1H), 7.58 (t, 2H), 4.73-4.84 (m, 1H), 3.60(t, 2H), 3.35 (br t, 2H), 2.21-2.30 (m, 1H), 1.04 (d, 3H), 0.97 (d, 3H).

Example 5384-Oxo-7-(2-oxoimidazolidin-1-yl)-N-[1,1,1-trifluoro-3-methylbutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Enantiomer 2)

LC-MS (Method 3): R_(t)=2.01 min; MS (ESIpos): m/z=528 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.41 (d, 1H), 9.00 (s, 1H), 8.59 (d,1H), 8.44 (d, 1H), 7.67 (s, 1H), 7.58 (t, 2H), 4.72-4.84 (m, 1H),3.56-3.63 (m, 2H), 3.31-3.39 (m, 2H), 2.21-2.30 (m, 1H), 1.04 (d, 3H),0.97 (d, 3H).

Example 539N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-(3-ethyl-2-oxotetrahydropyrimidin-1(2H)-yl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 60.0 mg (126 μmol) of the compound from Example 126Awere reacted with 19.4 mg (151 μmol) of1-ethyltetrahydropyrimidin-2(1H)-one in the presence of 26.1 mg (189μmol) of potassium carbonate, 5.66 mg (25.2 μmol) of palladium acetateand 14.6 mg (25.2 μmol) of Xantphos in 600 μl of 1,4-dioxane. The crudeproduct was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 25.0 mg (35% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.20 min; MS (ESIpos): m/z=568 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.33 (d, 1H), 9.00 (s, 1H), 8.51 (d,1H), 8.18 (d, 1H), 7.56-7.62 (m, 2H), 4.31-4.44 (m, 1H), 3.51 (t, 2H),3.32-3.39 (m, 3H), 1.87-1.94 (m, 2H), 1.18-1.27 (m, 1H), 1.08 (t, 3H),0.53-0.70 (m, 3H), 0.30-0.38 (m, 1H).

Example 5404-Oxo-7-(2-oxoimidazolidin-1-yl)-N-[3,3,4,4,4-pentafluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Racemate)

According to GP1, 500 mg (1.24 mmol) of the compound from Example 113Awere reacted with 282 mg (1.73 mmol) of the compound from Example 147Bin the presence of 564 mg (1.48 mmol) of HATU and 650 μl (3.70 mmol) ofDIPEA in 4.6 ml of DMF. The crude product was purified by means ofpreparative HPLC (acetonitrile/water/0.1% formic acid). 361 mg (53% oftheory, 100% purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.97 min; MS (ESIpos): m/z=550 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.33 (d, 1H), 9.00 (s, 1H), 8.55 (d,1H), 8.44 (d, 1H), 7.67 (s, 1H), 7.54-7.61 (m, 2H), 4.97-5.11 (m, 1H),3.54-3.65 (m, 2H), 3.32-3.38 (m, 2H), 1.41 (d, 3H).

358 mg of the title compound (racemate) were separated into theenantiomers by chiral SFC (preparative SFC: column: Daicel ChiralcelOD-H 5 μm 250×20 mm; eluent: 88% carbon dioxide, 12% isopropanol;temperature: 40° C.; flow rate: 80 ml/min; UV detection: 210 nm).

This gave (in the sequence of elution from the column) 111 mg (16% oftheory, 100% purity) of enantiomer 1 from Example 541 (99% ee) Rt=11.45min and 124 mg (18% of theory, 100% purity) of enantiomer 2 from Example542 (99% ee) Rt=13.60 min.

[Analytical SFC: column: OD; eluent: 80% carbon dioxide, 20%isopropanol; flow rate: 3.0 ml/min; UV detection: 210 nm].

Example 5414-Oxo-7-(2-oxoimidazolidin-1-yl)-N-[3,3,4,4,4-pentafluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Enantiomer 1)

LC-MS (Method 3): R_(t)=1.97 min; MS (ESIpos): m/z=550 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.33 (d, 1H), 9.00 (s, 1H), 8.55 (d,1H), 8.44 (d, 1H), 7.67 (s, 1H), 7.54-7.61 (m, 2H), 4.97-5.10 (m, 1H),3.55-3.63 (m, 2H), 3.32-3.38 (m, 2H), 1.41 (d, 3H).

Example 5424-Oxo-7-(2-oxoimidazolidin-1-yl)-N-[3,3,4,4,4-pentafluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Enantiomer 2)

LC-MS (Method 3): R_(t)=1.96 min; MS (ESIpos): m/z=550 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.33 (d, 1H), 9.00 (s, 1H), 8.55 (d,1H), 8.44 (d, 1H), 7.67 (s, 1H), 7.54-7.61 (m, 2H), 4.97-5.10 (m, 1H),3.55-3.63 (m, 2H), 3.32-3.38 (m, 2H), 1.41 (d, 3H).

Example 5434-Oxo-7-(2-oxoimidazolidin-1-yl)-N-[(2S)-1,1,1-trifluoro-4-methylpentan-2-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 26.0 mg (64.3 μmol) of the compound from Example 113Awere reacted with 12.0 mg (77.2 μmol) of(2S)-1,1,1-trifluoro-4-methylpentan-2-amine in the presence of 29.3 mg(77.2 μmol) of HATU and 34 μl (190 μmol) of DIPEA in 250 μl of DMF. Thecrude product was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 22.6 mg (65% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=2.16 min; MS (ESIpos): m/z=542 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.20 (d, 1H), 9.00 (s, 1H), 8.55 (d,1H), 8.44 (d, 1H), 7.67 (s, 1H), 7.54-7.61 (m, 2H), 4.78-4.89 (m, 1H),3.55-3.63 (m, 2H), 3.34-3.40 (m, 2H), 1.54-1.73 (m, 3H), 0.95 (d, 3H),0.90 (d, 3H).

Example 5447-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluoro-4-methylpentan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 50.0 mg (119 μmol) of the compound from Example 121Awere reacted with 22.1 mg (142 μmol) of(2S)-1,1,1-trifluoro-4-methylpentan-2-amine in the presence of 54.1 mg(142 μmol) of HATU and 62 μl (360 μmol) of DIPEA in 750 μl of DMF. Thecrude product was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 47.5 mg (67% of theory, 94%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.93 min; MS (ESIpos): m/z=559 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.42 (d, 1H), 8.81 (s, 1H), 8.27 (d,1H), 7.53-7.60 (m, 2H), 6.78 (d, 1H), 5.23 (d, 1H), 5.15 (d, 1H),4.77-4.88 (m, 1H), 4.05 (br s, 1H), 3.93 (br s, 1H), 3.62 (br dd, 1H),3.34 (br d, 1H), 3.25 (br dd, 1H), 3.07 (br d, 1H), 1.52-1.72 (m, 3H),0.95 (d, 3H), 0.89 (d, 3H).

Example 5457-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-N-[1,1,1,4,4,4-hexafluorobutan-2-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP1, 40.0 mg (94.9 μmol) of the compound from Example 121Awere reacted with 28.9 mg (133 μmol) of1,1,1,4,4,4-hexafluorobutan-2-amine hydrochloride in the presence of43.3 mg (114 μmol) of HATU and 50 μl (280 μmol) of DIPEA in 350 μl ofDMF. The crude product was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 32.0 mg (58% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.70 min; MS (ESIpos): m/z=585 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.71 (d, 1H), 8.83 (s, 1H), 8.27 (d,1H), 7.53-7.60 (m, 2H), 6.78 (d, 1H), 5.10-5.28 (m, 2H), 4.03-4.06 (m,1H), 3.91-3.94 (m, 1H), 3.58-3.64 (m, 1H), 3.34-3.39 (m, 1H), 3.20-3.28(m, 2H), 3.02-3.14 (m, 2H), 2.91-3.01 (m, 1H).

Example 546 1-(2-Chloro-4,6-difluorophenyl)-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Atropisomer Mixture)

According to GP3, 50.0 mg (102 μmol) of the compound from Example 110Awere reacted with 17.0 mg (122 μmol) of (3R,4R)-pyrrolidine-3,4-diolhydrochloride and 62 μl (360 μmol) of DIPEA in 500 μl of DMF. The crudeproduct was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 51.6 mg (91% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.76 min; MS (ESIpos): m/z=559 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.59 (d, 1H), 8.74 (s, 1H), 8.28 (d,1H), 7.66-7.76 (m, 2H), 6.78 (d, 1H), 5.20-5.26 (m, 1H), 5.12-5.17 (m,1H), 4.32-4.43 (m, 1H), 4.01-4.08 (m, 1H), 3.88-3.95 (m, 1H), 3.61 (brdd, 1H), 3.33-3.37 (m, 1H), 3.16-3.26 (m, 1H), 2.97-3.08 (m, 1H),1.14-1.25 (m, 1H), 0.49-0.69 (m, 3H), 0.34 (dt, 1H).

30.0 mg of the title compound (atropisomer mixture) were separated intothe atropisomers by chiral HPLC (preparative HPLC: column: DaicelChiralcel OX-H 5 μm 250×20 mm; eluent: 75% n-heptane, 25% isopropanol;temperature: 40° C.; flow rate: 15 ml/min; UV detection: 220 nm).

This gave (in the sequence of elution from the column) 14.0 mg (25% oftheory, 100% purity) of atropisomer 1 from Example 547 (99% de) Rt=6.08min and 13.0 mg (23% of theory, 100% purity) of atropisomer 2 fromExample 548 (99% de) Rt=8.82 min.

[Analytical HPLC: column: Daicel Chiralcel OX-H 5 μm 250×4.6 mm; eluent:70% isohexane, 30% isopropanol; temperature: 35° C.; flow rate: 1.0ml/min; UV detection: 220 nm]

Example 547 1-(2-Chloro-4,6-difluorophenyl)-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Atropisomer 1)

LC-MS (Method 3): R_(t)=1.77 min; MS (ESIpos): m/z=559 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.59 (d, 1H), 8.74 (s, 1H), 8.28 (d,1H), 7.66-7.76 (m, 2H), 6.78 (d, 1H), 5.19-5.26 (m, 1H), 5.10-5.19 (m,1H), 4.33-4.44 (m, 1H), 4.00-4.07 (m, 1H), 3.87-3.96 (m, 1H), 3.61 (brdd, 1H), 3.32-3.36 (m, 1H), 3.17-3.25 (m, 1H), 3.01 (br d, 1H),1.15-1.28 (m, 1H), 0.49-0.69 (m, 3H), 0.29-0.38 (m, 1H).

Example 548 1-(2-Chloro-4,6-difluorophenyl)-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Atropisomer 2)

LC-MS (Method 3): R_(t)=1.77 min; MS (ESIpos): m/z=559 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.59 (d, 1H), 8.74 (s, 1H), 8.28 (d,1H), 7.66-7.77 (m, 2H), 6.78 (d, 1H), 5.19-5.25 (m, 1H), 5.12-5.19 (m,1H), 4.32-4.42 (m, 1H), 4.04 (br s, 1H), 3.91 (br s, 1H), 3.61 (br dd,1H), 3.33-3.37 (m, 1H), 3.20 (br dd, 1H), 3.04 (br d, 1H), 1.16-1.26 (m,1H), 0.50-0.70 (m, 3H), 0.31-0.39 (m, 1H).

Example 5497-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-4-oxo-N-[3,3,4,4,4-pentafluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP1, 500 mg (1.19 mmol) of the compound from Example 121Awere reacted with 260 mg (1.31 mmol) of the compound from Example 147Bin the presence of 541 mg (1.42 mmol) of HATU and 830 μl (4.70 mmol) ofDIPEA in 5.0 ml of DMF. The crude product was purified by means ofpreparative HPLC (acetonitrile/water/0.1% formic acid). 399 mg (59% oftheory, 100% purity) of the title compound were obtained.

LC-MS (Method 1): R_(t)=0.93 min; MS (ESIpos): m/z=567 [M+H]⁺

¹H NMR (500 MHz, DMSO-d₆): δ ppm=10.56 (d, 1H), 8.80 (s, 1H), 8.27 (d,1H), 7.53-7.59 (m, 2H), 6.78 (d, 1H), 5.23 (t, 1H), 5.14 (t, 1H),4.96-5.07 (m, 1H), 4.05 (br s, 1H), 3.93 (br s, 1H), 3.58-3.65 (m, 1H),3.32-3.37 (m, 1H), 3.25 (dt, 1H), 3.07 (br d, 1H), 1.39 (d, 3H).

395 mg of the title compound (diastereomer mixture) were separated intothe diastereomers by chiral HPLC (preparative HPLC: column: DaicelChiralpak AD-H 5 μm 250×20 mm; eluent: 80% n-heptane, 20% isopropanol;temperature: 23° C.; flow rate: 20 ml/min; UV detection: 220 nm).

This gave (in the sequence of elution from the column) 164.7 mg (24% oftheory, 100% purity) of diastereomer 1 from Example 550 (99% de) Rt=4.52min and 163.7 mg (24% of theory, 100% purity) of diastereomer 2 fromExample 551 (97% de) Rt=6.81 min.

[Analytical HPLC: column: Daicel Chiralpak AD-3 3 μm 50×4.6 mm; eluent:80% n-heptane, 20% isopropanol; flow rate: 1.0 ml/min; UV detection: 220nm]

Example 5507-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-4-oxo-N-[3,3,4,4,4-pentafluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

LC-MS (Method 3): R_(t)=1.72 min; MS (ESIpos): m/z=567 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.56 (d, 1H), 8.81 (s, 1H), 8.27 (d,1H), 7.53-7.60 (m, 2H), 6.78 (d, 1H), 5.23 (d, 1H), 5.15 (d, 1H),4.95-5.09 (m, 1H), 4.05 (br s, 1H), 3.93 (br s, 1H), 3.62 (dd, 1H), 3.33(br d, 1H), 3.24 (dd, 1H), 3.07 (br d, 1H), 1.39 (d, 3H).

Example 5517-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-4-oxo-N-[3,3,4,4,4-pentafluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2)

LC-MS (Method 3): R_(t)=1.72 min; MS (ESIpos): m/z=567 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.56 (d, 1H), 8.81 (s, 1H), 8.27 (d,1H), 7.52-7.60 (m, 2H), 6.78 (d, 1H), 5.24 (d, 1H), 5.14 (d, 1H),4.96-5.09 (m, 1H), 4.05 (br s, 1H), 3.93 (br s, 1H), 3.61 (dd, 1H),3.32-3.37 (m, 1H), 3.25 (dd, 1H), 3.07 (d, 1H), 1.39 (d, 3H).

Example 5527-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-4-oxo-N-[1,1,1-trifluoro-3-methylbutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP1, 80 mg (190 μmol) of the compound from Example 121Awere reacted with 32.2 mg (228 μmol) of1,1,1-trifluoro-3-methylbutan-2-amine in the presence of 86.6 mg (228μmol) of HATU and 99 μl (570 μmol) of DIPEA in 1.4 ml of DMF. The crudeproduct was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 73.4 mg (71% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.76 min; MS (ESIpos): m/z=545 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.62 (d, 1H), 8.81 (s, 1H), 8.30 (d,1H), 7.57 (br t, 2H), 6.78 (d, 1H), 5.24 (t, 1H), 5.14 (t, 1H),4.71-4.81 (m, 1H), 4.05 (br s, 1H), 3.93 (br s, 1H), 3.62 (br dd, 1H),3.32-3.37 (m, 1H), 3.25 (br dd, 1H), 3.07 (br d, 1H), 2.19-2.29 (m, 1H),1.03 (d, 3H), 0.96 (d, 3H).

51.0 mg of the title compound (diastereomer mixture) were separated intothe diastereomers by chiral HPLC (preparative HPLC: column: DaicelChiralpak IF 5 m 250×20 mm; eluent: 80% n-heptane, 20% isopropanol;temperature: 23° C.; flow rate: 20 ml/min; UV detection: 270 nm).

This gave (in the sequence of elution from the column) 7.40 mg ofdiastereomer 1 (99% de) Rt=7.55 min and 7.30 mg of diastereomer 2 (96%de) Rt=9.20 min.

[Analytical HPLC: column: Daicel Chiralpak IE-3 3 m 50×4.6 mm; eluent:80% n-heptane, 20% isopropanol; temperature: 30° C.; flow rate: 1.0ml/min; UV detection: 220 nm]

Diastereomer 1 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125*40 mm, solvent: acetonitrile,water, 0.1% formic acid), and 2.40 mg (2.3% of theory, 100% purity) ofthe title compound from Example 553 were obtained.

Diastereomer 2 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125*40 mm, solvent: acetonitrile,water, 0.1% formic acid), and 2.30 mg (2.2% of theory, 100% purity) ofthe title compound from Example 554 were obtained.

Example 5537-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-4-oxo-N-[1,1,1-trifluoro-3-methylbutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

LC-MS (Method 3): R_(t)=1.77 min; MS (ESIpos): m/z=545 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.62 (d, 1H), 8.81 (s, 1H), 8.30 (d,1H), 7.53-7.60 (m, 2H), 6.78 (d, 1H), 5.23 (d, 1H), 5.15 (d, 1H),4.71-4.82 (m, 1H), 4.05 (br s, 1H), 3.93 (br s, 1H), 3.62 (br dd, 1H),3.32-3.37 (m, 1H), 3.25 (br dd, 1H), 3.07 (d, 1H), 2.19-2.29 (m, 1H),1.03 (d, 3H), 0.97 (d, 3H).

Example 5547-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-4-ox-N-[1,1,1-trifluoro-3-methylbutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2)

LC-MS (Method 3): R_(t)=1.77 min; MS (ESIpos): m/z=545 [M+H]⁺

¹H NMR (500 MHz, DMSO-d₆): δ ppm=10.62 (br d, 1H), 8.81 (s, 1H), 8.30(br d, 1H), 7.56 (br t, 2H), 6.78 (br d, 1H), 5.19-5.26 (m, 1H),5.12-5.19 (m, 1H), 4.72-4.81 (m, 1H), 4.05 (br s, 1H), 3.93 (br s, 1H),3.57-3.66 (m, 1H), 3.33-3.38 (m, 1H), 3.22-3.27 (m, 1H), 3.07 (br d,1H), 2.19-2.29 (m, 1H), 1.03 (br d, 3H), 0.97 (br d, 3H).

Example 555N-(1,1,1,3,3,3-Hexafluoropropan-2-yl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 60.0 mg (119 μmol) of the compound from Example 154Awere reacted with 14.5 mg (143 μmol) of (4S)-4-hydroxypyrrolidin-2-onein the presence of 24.7 mg (179 μmol) of potassium carbonate, 5.35 mg(23.8 μmol) of palladium acetate and 13.8 mg (23.8 μmol) of Xantphos in1.2 ml of 1,4-dioxane. The crude product was purified by means ofpreparative HPLC (acetonitrile/water/0.1% formic acid). 42.3 mg (62% oftheory, 100% purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.99 min; MS (ESIpos): m/z=569 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=11.03 (d, 1H), 9.20 (s, 1H), 8.74 (d,1H), 8.56 (d, 1H), 7.59-7.67 (m, 2H), 6.33-6.43 (m, 1H), 5.34 (d, 1H),4.27-4.32 (m, 1H), 3.69 (dd, 1H), 3.48 (d, 1H), 2.95 (dd, 1H), 2.38 (d,1H).

Example 5561-(2,4-Difluorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[1,1,1,2,2-pentafluoropentan-3-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP1, 100 mg (249 μmol) of the compound from Example 63Awere reacted with 63.9 mg (299 μmol) of the compound from Example 153Bin the presence of 114 mg (299 μmol) of HATU and 170 μl (1000 μmol) ofDIPEA in 1.0 ml of DMF. The crude product was purified by means ofpreparative HPLC (acetonitrile/water/0.1% formic acid). 123 mg (88% oftheory, 100% purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.96 min; MS (ESIpos): m/z=561 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.27 (d, 1H), 8.86 (d, 1H), 8.71 (d,1H), 8.52 (br dd, 1H), 7.83-7.94 (m, 1H), 7.63 (br t, 1H), 7.37 (br t,1H), 5.27-5.37 (m, 1H), 4.82-4.96 (m, 1H), 4.25-4.31 (m, 1H), 3.66 (td,1H), 3.47 (br t, 1H), 2.88-3.00 (m, 1H), 2.37 (br dd, 1H), 1.88-1.99 (m,1H), 1.62-1.74 (m, 1H), 0.97 (br t, 3H).

95.0 mg of the title compound (diastereomer mixture) were separated intothe diastereomers by chiral HPLC (preparative HPLC: column: DaicelChiralpak IE 5 m 250×30 mm; eluent: 70% n-heptane, 20% isopropanol;temperature: 23° C.; flow rate: 20 ml/min; UV detection: 220 nm).

This gave (in the sequence of elution from the column) 35.1 mg (25% oftheory, 100% purity) of diastereomer 1 from Example 557 (99% de) Rt=7.05min and 34.9 mg (25% of theory, 100% purity) of diastereomer 2 fromExample 558 (99% de) Rt=9.72 min.

[Analytical HPLC: column: Daicel Chiralpak IE-3 3 m 50×4.6 mm; eluent:80% n-heptane, 20% isopropanol; temperature: 30° C.; flow rate: 1.0ml/min; UV detection: 220 nm]

Example 5571-(2,4-Difluorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[1,1,1,2,2-pentafluoropentan-3-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

LC-MS (Method 3): R_(t)=1.97 min; MS (ESIpos): m/z=561 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.27 (d, 1H), 8.86 (d, 1H), 8.71 (d,1H), 8.52 (dd, 1H), 7.83-7.94 (m, 1H), 7.59-7.66 (m, 1H), 7.33-7.40 (m,1H), 5.28-5.37 (m, 1H), 4.83-4.96 (m, 1H), 4.26-4.31 (m, 1H), 3.66 (td,1H), 3.47 (br t, 1H), 2.89-2.99 (m, 1H), 2.32-2.41 (m, 1H), 1.88-1.98(m, 1H), 1.62-1.74 (m, 1H), 0.97 (t, 3H).

Example 5581-(2,4-Difluorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[1,1,122-pentafluoropentan-3-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2)

LC-MS (Method 3): R_(t)=1.97 min; MS (ESIpos): m/z=561 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.27 (d, 1H), 8.86 (d, 1H), 8.71 (d,1H), 8.52 (dd, 1H), 7.84-7.92 (m, 1H), 7.63 (br t, 1H), 7.37 (br t, 1H),5.18-5.43 (m, 1H), 4.82-4.96 (m, 1H), 4.28 (br t, 1H), 3.59-3.72 (m,1H), 3.42-3.52 (m, 1H), 2.94 (ddd, 1H), 2.32-2.42 (m, 1H), 1.88-1.99 (m,1H), 1.62-1.74 (m, 1H), 0.97 (t, 3H).

Example 5597-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-4-oxo-N-[(2S)-1,1,1-trifluoro-4-methylpentan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 50.0 mg (119 μmol) of the compound from Example 121Awere reacted with 22.1 mg (142 μmol) of(2R)-1,1,1-trifluoro-4-methylpentan-2-amine in the presence of 54.1 mg(142 μmol) of HATU and 62 μl (360 μmol) of DIPEA in 750 μl of DMF. Thecrude product was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 47.5 mg (72% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.93 min; MS (ESIpos): m/z=559 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.42 (d, 1H), 8.81 (s, 1H), 8.27 (d,1H), 7.52-7.60 (m, 2H), 6.78 (d, 1H), 5.24 (d, 1H), 5.14 (d, 1H),4.77-4.88 (m, 1H), 4.05 (br s, 1H), 3.93 (br s, 1H), 3.61 (br dd, 1H),3.34 (br d, 1H), 3.25 (br dd, 1H), 3.07 (br d, 1H), 1.52-1.72 (m, 3H),0.95 (d, 3H), 0.89 (d, 3H).

Example 560N-[1-(2-Chlorophenyl)-2,2,2-trifluoroethyl]-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP1, 50.0 mg (119 μmol) of the compound from Example 121Awere reacted with 29.8 mg (142 μmol) of1-(2-chlorophenyl)-2,2,2-trifluoroethanamine in the presence of 54.1 mg(142 μmol) of HATU and 62 μl (360 μmol) of DIPEA in 460 μl of DMF. Thecrude product was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 44.9 mg (61% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.97 min; MS (ESIpos): m/z=613 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=11.56 (d, 1H), 8.83 (s, 1H), 8.32 (d,1H), 7.48-7.64 (m, 6H), 6.80 (d, 1H), 6.40-6.49 (m, 1H), 5.08-5.30 (m,2H), 4.03-4.07 (m, 1H), 3.90-3.95 (m, 1H), 3.58-3.65 (m, 1H), 3.03-3.10(m, 1H), 0.97-1.04 (m, 2H).

37.6 mg of the title compound (diastereomer mixture) were separated intothe diastereomers by chiral HPLC (preparative HPLC: column: DaicelChiralcel OX-H 5 m 250×20 mm; eluent: 45% n-heptane, 55% isopropanol;temperature: 40° C.; flow rate: 15 ml/min; UV detection: 220 nm).

This gave (in the sequence of elution from the column) 14.0 mg (19% oftheory, 100% purity) of diastereomer 1 from Example 561 (99% de) Rt=4.83min and 15.0 mg (20% of theory, 100% purity) of diastereomer 2 fromExample 562 (99% de) Rt=6.63 min.

[Analytical HPLC: column: Daicel Chiralcel OX-H 5 m 250×4.6 mm; eluent:50% isohexane, 50% isopropanol; temperature: 45° C.; flow rate: 1.0ml/min; UV detection: 220 nm]

Example 561N-[1-(2-Chlorophenyl)-2,2,2-trifluoroethyl]-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

LC-MS (Method 3): R_(t)=1.95 min; MS (ESIpos): m/z=613 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=11.56 (d, 1H), 8.83 (s, 1H), 8.32 (d,1H), 7.48-7.64 (m, 6H), 6.80 (d, 1H), 6.40-6.49 (m, 1H), 5.23 (d, 1H),5.15 (d, 1H), 4.05 (br s, 1H), 3.90-3.95 (m, 1H), 3.62 (dd, 1H),3.33-3.38 (m, 1H), 3.24 (br dd, 1H), 3.07 (br d, 1H).

Example 562N-[1-(2-Chlorophenyl)-2,2,2-trifluoroethyl]-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2)

LC-MS (Method 3): R_(t)=1.96 min; MS (ESIpos): m/z=613 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=11.56 (d, 1H), 8.83 (s, 1H), 8.32 (d,1H), 7.48-7.64 (m, 6H), 6.80 (d, 1H), 6.40-6.49 (m, 1H), 5.24 (d, 1H),5.14 (d, 1H), 4.05 (br s, 1H), 3.93 (br s, 1H), 3.62 (br dd, 1H),3.33-3.38 (m, 1H), 3.25 (dd, 1H), 3.06 (d, 1H).

Example 563N-[1-(2-Chlorophenyl)-2,2,2-trifluoroethyl]-4-oxo-7-(2-oxoimidazolidin-1-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Racemate)

According to GP1, 50.0 mg (124 μmol) of4-oxo-7-(2-oxoimidazolidin-1-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid (Example 113A) were reacted with 31.1 mg (148 μmol) of1-(2-chlorophenyl)-2,2,2-trifluoroethanamine in the presence of 56.4 mg(148 μmol) of HATU and 65 μl (370 μmol) of DIPEA in 480 μl of DMF. Thecrude product was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 50.6 mg (69% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.16 min; MS (ESIpos): m/z=596 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=11.32 (d, 1H), 9.01 (s, 1H), 8.60 (d,1H), 8.46 (d, 1H), 7.48-7.69 (m, 7H), 6.41-6.50 (m, 1H), 3.55-3.64 (m,2H), 3.34-3.38 (m, 2H). 40.4 mg of the title compound (racemate) wereseparated into the enantiomers by chiral HPLC (preparative HPLC: column:Daicel Chiralpak AZ-H 5 m 250×20 mm; eluent: 25% n-heptane, 75%isopropanol; temperature: 25° C.; flow rate: 15 ml/min; UV detection:210 nm).

This gave (in the sequence of elution from the column) 19.3 mg ofenantiomer 1 (99% ee) Rt=8.40 min and 16.8 mg of enantiomer 2 (99% ee)Rt=17.95 min.

[Analytical HPLC: column: Chiraltek AZ-3 3 μm; eluent: 50% isohexane,50% isopropanol; UV detection: 220 nm].

Enantiomer 1 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125*40 mm, solvent: acetonitrile,water, 0.1% formic acid), and 11.5 mg (16% of theory, 97% purity) of thetitle compound from Example 564 were obtained.

Enantiomer 2 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125*40 mm, solvent: acetonitrile,water, 0.1% formic acid), and 9.30 mg (13% of theory, 100% purity) ofthe title compound from Example 565 were obtained.

Example 564N-[1-(2-Chlorophenyl)-2,2,2-trifluoroethyl]-4-oxo-7-(2-oxoimidazolidin-1-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Enantiomer 2)

LC-MS (Method 4): R_(t)=3.81 min; MS (ESIpos): m/z=596 [M+H]⁺

¹H NMR (500 MHz, DMSO-d₆): δ ppm=11.32 (d, 1H), 9.01 (s, 1H), 8.60 (d,1H), 8.46 (d, 1H), 7.49-7.68 (m, 7H), 6.42-6.49 (m, 1H), 3.56-3.62 (m,2H), 3.33-3.37 (m, 2H).

Example 565N-[1-(2-Chlorophenyl)-2,2,2-trifluoroethyl]-4-oxo-7-(2-oxoimidazolidin-1-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Enantiomer 2)

LC-MS (Method 3): R_(t)=2.17 min; MS (ESIpos): m/z=596 [M+H]⁺

¹H NMR (500 MHz, DMSO-d₆): δ ppm=11.32 (d, 1H), 9.01 (s, 1H), 8.60 (d,1H), 8.46 (d, 1H), 7.49-7.68 (m, 7H), 6.42-6.49 (m, 1H), 3.56-3.63 (m,2H), 3.32-3.37 (m, 2H).

Example 5661-(2-Chloro-4,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Atropisomer Mixture)

According to GP3, 50.0 mg (104 μmol) of the compound from Example 108Cwere reacted with 17.4 mg (125 μmol) of (3R,4R)-pyrrolidine-3,4-diolhydrochloride and 63 μl (360 μmol) of DIPEA in 500 μl of DMF. The crudeproduct was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 50.0 mg (88% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.72 min; MS (ESIpos): m/z=547 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.46 (dd, 1H), 8.75 (s, 1H), 8.28 (d,1H), 7.67-7.76 (m, 2H), 6.77 (d, 1H), 5.23 (br d, 1H), 5.14 (d, 1H),4.68-4.79 (m, 1H), 4.04 (br s, 1H), 3.92 (br s, 1H), 3.61 (br dd, 1H),3.32-3.37 (m, 1H), 3.17-3.25 (m, 1H), 3.02 (br dd, 1H), 1.83-1.93 (m,1H), 1.59-1.71 (m, 1H), 0.94-1.00 (m, 3H).

30.0 mg of the title compound (atropisomer mixture) were separated intothe atropisomers by chiral HPLC (preparative HPLC: column: DaicelChiralcel OX-H 5 m 250×20 mm; eluent: 75% n-heptane, 25% isopropanol;temperature: 40° C.; flow rate: 15 ml/min; UV detection: 220 nm).

This gave (in the sequence of elution from the column) 13.0 mg (23% oftheory, 100% purity) of atropisomer 1 from Example 567 (99% de) Rt=6.73min and 10.0 mg (18% of theory, 100% purity) of atropisomer 2 fromExample 568 (99% de) Rt=11.48 min.

[Analytical HPLC: column: Daicel Chiralcel OX-H 5 μm 250×4.6 mm; eluent:70% isohexane, 30% isopropanol; temperature: 35° C.; flow rate: 1.0ml/min; UV detection: 220 nm]

Example 5671-(2-Chloro-4,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Atropisomer 1)

LC-MS (Method 3): R_(t)=1.73 min; MS (ESIpos): m/z=547 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.46 (d, 1H), 8.75 (s, 1H), 8.28 (d,1H), 7.67-7.76 (m, 2H), 6.77 (d, 1H), 5.23 (d, 1H), 5.14 (d, 1H),4.68-4.80 (m, 1H), 4.04 (br s, 1H), 3.92 (br s, 1H), 3.61 (dd, 1H),3.32-3.37 (m, 1H), 3.22 (br dd, 1H), 3.01 (d, 1H), 1.82-1.94 (m, 1H),1.58-1.70 (m, 1H), 0.97 (t, 3H).

Example 5681-(2-Chloro-4,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Atropisomer 2)

LC-MS (Method 3): R_(t)=1.73 min; MS (ESIpos): m/z=547 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.45 (d, 1H), 8.75 (s, 1H), 8.28 (d,1H), 7.68-7.75 (m, 2H), 6.77 (d, 1H), 5.23 (d, 1H), 5.14 (d, 1H),4.68-4.79 (m, 1H), 4.04 (br s, 1H), 3.87-3.94 (m, 1H), 3.57-3.65 (m,1H), 3.32-3.38 (m, 1H), 3.20 (br dd, 1H), 3.04 (br d, 1H), 1.83-1.93 (m,1H), 1.59-1.71 (m, 1H), 0.98 (t, 3H).

Example 5697-[7-Hydroxy-5-azaspiro[2.4]hept-5-yl]-4-oxo-N-(4,4,4-trifluoro-2-methylbutan-2-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Racemate)

According to GP1, 80.0 mg (185 μmol) of the compound from Example 155Awere reacted with 39.5 mg (223 μmol) of4,4,4-trifluoro-2-methylbutan-2-amine hydrochloride in the presence of84.6 mg (223 μmol) of HATU and 97 μl (560 μmol) of DIPEA in 890 μl ofDMF. The crude product was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 80.9 mg (79% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 4): R_(t)=3.60 min; MS (ESIpos): m/z=555 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.16 (s, 1H), 8.66-8.71 (m, 1H), 8.27(d, 1H), 7.49-7.60 (m, 2H), 6.78 (br d, 0.40H), 6.66 (br d, 0.60H), 5.06(br s, 0.40H), 4.97 (br d, 0.60H), 3.59-3.78 (m, 2H), 3.36-3.49 (m, 1H),3.10-3.26 (min, 2H), 2.95 (q, 2H), 1.48 (s, 6H), 0.82 (br t, 1H),0.54-0.62 (m, 2H), 0.48 (br s, 1H).

76.6 mg of the title compound (racemate) were separated into theenantiomers by chiral HPLC (preparative HPLC: column: YMC ChiralartAmylose SA 5 μm 250×30 mm; eluent: 80% n-heptane, 20% ethanol;temperature: 25° C.; flow rate: 30 ml/min; UV detection: 220 nm).

This gave (in the sequence of elution from the column) 30.0 mg (29% oftheory, 100% purity) of enantiomer 1 from Example 570 (99% ee) Rt=9.31min and 32.0 mg (31% of theory, 100% purity) of enantiomer 2 fromExample 571 (99% ee) Rt=11.08 min.

[Analytical HPLC: column: YMC Chiralart Amylose SA 5 μm 250×4.6 mm;eluent: 80% isohexane, 20% ethanol; temperature: 25° C.; flow rate: 1.0ml/min; UV detection: 220 nm]

Example 5707-[7-Hydroxy-5-azaspiro[2.4]hept-5-yl]-4-oxo-N-(4,4,4-trifluoro-2-methylbutan-2-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Enantiomer 1)

LC-MS (Method 1): R_(t)=1.12 min; MS (ESIpos): m/z=555 [M+H]⁺

¹H NMR (500 MHz, DMSO-d₆): δ ppm=10.16 (s, 1H), 8.66-8.70 (m, 1H), 8.27(d, 1H), 7.49-7.59 (m, 2H), 6.78 (br d, 0.40H), 6.66 (br d, 0.60H),5.02-5.08 (m, 0.40H), 4.97 (br d, 0.60H), 3.60-3.78 (m, 2H), 3.31-3.47(m, 2H), 3.20 (br dd, 1H), 2.95 (q, 2H), 1.48 (s, 6H), 0.77-0.87 (m,1H), 0.53-0.62 (m, 2H), 0.48 (br s, 1H).

Example 5717-[7-Hydroxy-5-azaspiro[2.4]hept-5-yl]-4-oxo-N-(4,4,4-trifluoro-2-methylbutan-2-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Enantiomer 2)

LC-MS (Method 1): R_(t)=1.12 min; MS (ESIpos): m/z=555 [M+H]⁺

¹H NMR (500 MHz, DMSO-d₆): δ ppm=10.16 (s, 1H), 8.66-8.70 (m, 1H), 8.27(d, 1H), 7.49-7.59 (m, 2H), 6.78 (br d, 0.40H), 6.66 (br d, 0.60H), 5.07(br s, 0.40H), 4.97 (br s, 0.60H), 3.60-3.77 (m, 2H), 3.33-3.47 (m, 2H),3.20 (br dd, 1H), 2.95 (q, 2H), 1.48 (s, 6H), 0.77-0.86 (m, 1H),0.54-0.62 (m, 2H), 0.45-0.54 (m, 1H).

Example 5727-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-N-(1,1,1,3,3,3-hexafluoropropan-2-yl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP3, 60.0 mg (119 μmol) of the compound from Example 154Awere reacted with 20.0 mg (143 μmol) of (3R,4R)-pyrrolidine-3,4-diolhydrochloride and 73 μl (420 μmol) of DIPEA in 600 μl of DMF. The crudeproduct was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 58.9 mg (87% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.83 min; MS (ESIpos): m/z=571 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=11.41 (d, 1H), 8.94 (s, 1H), 8.30 (d,1H), 7.53-7.62 (m, 2H), 6.81 (d, 1H), 6.24-6.37 (m, 1H), 5.24 (d, 1H),5.15 (d, 1H), 4.05 (br s, 1H), 3.93 (br s, 1H), 3.62 (br dd, 1H),3.33-3.39 (m, 1H), 3.20-3.28 (m, 1H), 3.07 (br d, 1H).

Example 5737-[(3R,4S)-3,4-Dihydroxypyrrolidin-1-yl]-4-oxo-N-[(2S)-1,1,1-trifluoro-4-methylpentan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 60.0 mg (142 μmol) of the compound from Example 156Awere reacted with 26.5 mg (171 μmol) of(2S)-1,1,1-trifluoro-4-methylpentan-2-amine in the presence of 65.0 mg(171 μmol) of HATU and 74 μl (430 μmol) of DIPEA in 1.2 ml of DMF. Thecrude product was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 46.5 mg (58% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.97 min; MS (ESIpos): m/z=559 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.41 (br d, 1H), 8.81 (s, 1H), 8.27(d, 1H), 7.52-7.61 (m, 2H), 6.76 (d, 1H), 4.99-5.07 (m, 1H), 4.94 (br d,1H), 4.76-4.88 (m, 1H), 4.09-4.17 (m, 1H), 3.99-4.07 (m, 1H), 3.56-3.64(m, 1H), 3.18-3.28 (m, 2H), 2.96-3.05 (m, 1H), 1.62-1.72 (m, 2H),1.52-1.62 (m, 1H), 0.95 (br d, 3H), 0.89 (br d, 3H).

Example 5747-[(3R,4S)-3,4-Dihydroxypyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluoro-4-methylpentan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 60.0 mg (142 μmol) of the compound from Example 156Awere reacted with 26.5 mg (171 μmol) of(2R)-1,1,1-trifluoro-4-methylpentan-2-amine in the presence of 65.0 mg(171 μmol) of HATU and 74 μl (430 μmol) of DIPEA in 1.2 ml of DMF. Thecrude product was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 18.2 mg (23% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.97 min; MS (ESIpos): m/z=559 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.33-10.50 (m, 1H), 8.81 (br s, 1H),8.19-8.34 (m, 1H), 7.46-7.66 (m, 2H), 6.68-6.84 (m, 1H), 4.78-5.07 (m,3H), 3.94-4.21 (m, 2H), 3.53-3.66 (m, 1H), 2.95-3.08 (m, 1H), 1.49-1.76(m, 3H), 0.82-1.02 (m, 6H).

Example 575 Methyl4-{5-oxo-6-[(4,4,4-trifluoro-2-methylbutan-2-yl)carbamoyl]-8-(2,4,6-trifluorophenyl)-5,8-dihydro-1,8-naphthyridin-2-yl}piperazine-1-carboxylate

According to GP1, 70.0 mg (151 μmol) of the compound from Example 157Awere reacted with 32.3 mg (182 μmol) of4,4,4-trifluoro-2-methylbutan-2-amine hydrochloride in the presence of69.1 mg (182 μmol) of HATU and 110 μl (610 μmol) of DIPEA in 580 μl ofDMF. The crude product was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 61.1 mg (69% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=2.14 min; MS (ESIpos): m/z=586 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.10 (s, 1H), 8.72 (s, 1H), 8.31 (d,1H), 7.56 (t, 2H), 7.11 (d, 1H), 3.60 (s, 3H), 3.48-3.55 (m, 4H),3.36-3.43 (m, 4H), 2.95 (q, 2H), 1.48 (s, 6H).

Example 5767-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-4-oxo-N-[1-(trifluoromethoxy)butan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP1, 500 mg (1.19 mmol) of the compound from Example 121Awere reacted with 276 mg (1.42 mmol) of1-(trifluoromethoxy)butan-2-amine hydrochloride in the presence of 541mg (1.42 mmol) of HATU and 830 μl (4.70 mmol) of DIPEA in 5.0 ml of DMF.The crude product was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 389 mg (58% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 1): R_(t)=0.94 min; MS (ESIpos): m/z=561 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.08 (br d, 1H), 8.72 (s, 1H), 8.27(d, 1H), 7.52-7.60 (m, 2H), 6.76 (d, 1H), 5.23 (d, 1H), 5.13 (d, 1H),4.13-4.23 (m, 3H), 4.05 (br s, 1H), 3.92 (br s, 1H), 3.61 (br dd, 1H),3.32-3.36 (m, 1H), 3.25 (br dd, 1H), 3.07 (br d, 1H), 1.53-1.73 (m, 2H),0.94 (t, 3H).

385 mg of the title compound (diastereomer mixture) were separated intothe diastereomers by chiral HPLC (preparative HPLC: column: DaicelChiralcel OZ-H 5 μm 250×20 mm; eluent: 80% n-heptane, 20% isopropanol;temperature: 23° C.; flow rate: 20 ml/min; UV detection: 220 nm).

This gave (in the sequence of elution from the column) 119.4 mg ofdiastereomer 1 (99% de) Rt=5.13 min and 96.4 mg of diastereomer 2 (95%de) Rt=6.74 min.

[Analytical HPLC: column: Daicel OZ-3 3 μm 50×4.6 mm; eluent: 80%isohexane, 20% isopropanol; UV detection: 220 nm].

Diastereomer 1 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125*40 mm, solvent: acetonitrile,water, 0.1% formic acid). The isolated substance contained impuritiesand was further recrystallized from acetonitrile, filtered off withsuction, washed with a little acetonitrile and dried. 89.3 mg (13% oftheory, 100% purity) of the title compound from Example 577 wereobtained.

Diastereomer 2 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125*40 mm, solvent: acetonitrile,water, 0.1% formic acid). The isolated substance contained impuritiesand was further recrystallized from acetonitrile, filtered off withsuction, washed with a little acetonitrile and dried. 75.5 mg (11% oftheory, 100% purity) of the title compound from Example 578 wereobtained.

Example 5777-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-4-oxo-N-[1-(trifluoromethoxy)butan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

LC-MS (Method 1): R_(t)=0.92 min; MS (ESIpos): m/z=561 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.04-10.11 (m, 1H), 8.72 (s, 1H), 8.27(d, 1H), 7.52-7.60 (m, 2H), 6.76 (d, 1H), 5.23 (d, 1H), 5.13 (d, 1H),4.13-4.23 (m, 3H), 4.05 (br s, 1H), 3.92 (br s, 1H), 3.61 (br dd, 1H),3.32-3.37 (m, 1H), 3.25 (br dd, 1H), 3.07 (br d, 1H), 1.54-1.73 (m, 2H),0.94 (t, 3H).

Example 5787-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-4-oxo-N-[1-(trifluoromethoxy)butan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2)

LC-MS (Method 1): R_(t)=0.92 min; MS (ESIpos): m/z=561 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.08 (br d, 1H), 8.72 (s, 1H), 8.27(d, 1H), 7.52-7.60 (m, 2H), 6.76 (d, 1H), 5.22 (d, 1H), 5.13 (d, 1H),4.13-4.23 (m, 3H), 4.05 (br s, 1H), 3.89-3.96 (m, 1H), 3.61 (br dd, 1H),3.32-3.37 (m, 1H), 3.25 (br dd, 1H), 3.07 (br d, 1H), 1.53-1.73 (m, 2H),0.94 (t, 3H).

Example 579 N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[4-hydroxy-3-methyl-2-oxopyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP2, 130 mg (273 μmol) of the compound from Example 126Awere reacted with 37.8 mg (328 μmol) of the compound 158D in thepresence of 56.6 mg (410 μmol) of potassium carbonate, 12.3 mg (54.6μmol) of palladium acetate and 31.6 mg (54.6 μmol) of Xantphos in 2.4 mlof 1,4-dioxane. The crude product was purified by means of preparativeHPLC (acetonitrile/water/0.1% formic acid). The isolated substancecontained impurities and was further recrystallized from acetonitrile,filtered off with suction, washed with a little acetonitrile and dried.79.6 mg (51% of theory, 97% purity) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.06 min; MS (ESIpos): m/z=555 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.22-10.30 (m, 1H), 9.06 (s, 1H), 8.71(d, 1H), 8.51-8.58 (m, 1H), 7.57-7.66 (m, 2H), 5.50 (d, 0.20H), 5.24 (d,0.80H), 4.40 (sxt, 1H), 4.19 (q, 0.80H), 3.90-3.96 (m, 0.20H), 3.77 (dd,0.20H), 3.56-3.64 (m, 0.80H), 3.47-3.53 (m, 0.80H), 3.25 (dd, 0.20H),2.80-2.88 (m, 0.80H), 1.18-1.28 (m, 1H), 1.14 (d, 0.60H), 1.08 (d,2.40H), 0.52-0.70 (m, 3H), 0.30-0.39 (m, 1H).

Example 5804-Oxo-7-(2-oxoimidazolidin-1-yl)-N-[(2R)-1,1,1-trifluoro-4-methylpentan-2-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 50.0 mg (124 μmol) of the compound from Example 113Awere reacted with 23.0 mg (148 μmol) of(2R)-1,1,1-trifluoro-4-methylpentan-2-amine in the presence of 56.4 mg(148 μmol) of HATU and 65 μl (370 μmol) of DIPEA in 480 μl of DMF. Thecrude product was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 36.2 mg (54% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=2.16 min; MS (ESIpos): m/z=542 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.20 (d, 1H), 9.00 (s, 1H), 8.55 (d,1H), 8.44 (d, 1H), 7.67 (s, 1H), 7.57 (t, 2H), 4.80-4.89 (m, 1H),3.56-3.62 (m, 2H), 3.32-3.38 (m, 2H), 1.64-1.74 (m, 2H), 1.53-1.62 (m,1H), 0.95 (d, 3H), 0.90 (d, 3H).

Example 581N-(1,1,1,3,3,3-Hexafluoro-2-methylpropan-2-yl)-4-oxo-7-(2-oxoimidazolidin-1-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 22.0 mg (42.5 μmol) of the compound from Example 159Awere reacted with 36.6 mg (425 μmol) of imidazolidin-2-one in thepresence of 8.81 mg (63.7 μmol) of potassium carbonate, 1.91 mg (8.50μmol) of palladium acetate and 4.92 mg (8.50 μmol) of Xantphos in 430 μlof 1,4-dioxane. The crude product was purified by means of preparativeHPLC (acetonitrile/water/0.1% formic acid). 5.30 mg (22% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=2.12 min; MS (ESIpos): m/z=568 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=11.36 (s, 1H), 9.04 (s, 1H), 8.59 (d,1H), 8.45 (d, 1H), 7.69 (s, 1H), 7.58 (t, 2H), 3.53-3.65 (m, 2H),3.32-3.38 (m, 2H), 2.07 (s, 3H).

Example 582 N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[trans-3-hydroxy-4-methoxypyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP3, 150 mg (315 μmol) of the compound from Example 126Awere reacted with 44.3 mg (378 μmol) of 4-methoxypyrrolidin-3-ol and 160μl (950 μmol) of DIPEA in 1.3 ml of DMF. The crude product was purifiedby means of preparative HPLC (acetonitrile/water/0.1% formic acid). 147mg (84% of theory, 100% purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.95 min; MS (ESIpos): m/z=557 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.56 (d, 1H), 8.80 (s, 1H), 8.29 (d,1H), 7.52-7.60 (m, 2H), 6.80 (t, 1H), 5.35 (br s, 0.45H), 5.25 (br s,0.55H), 4.33-4.44 (m, 1H), 4.27 (br s, 0.45H), 4.14 (br s, 0.55H), 3.79(br s, 0.55H), 3.69 (br s, 0.45H), 3.50-3.64 (m, 1.55H), 3.35-3.40 (m,0.45H), 3.26 (br d, 3.45H), 3.19 (br d, 1H), 3.05-3.12 (m, 0.55H),1.16-1.25 (m, 1H), 0.50-0.69 (m, 3H), 0.31-0.38 (m, 1H).

138 mg of the title compound (diastereomer mixture) were separated intothe diastereomers by chiral HPLC (preparative HPLC: column: DaicelChiralpak IA 5 μm 250×20 mm; eluent: 85% n-heptane, 15% ethanol;temperature: 25° C.; flow rate: 15 ml/min; UV detection: 210 nm).

This gave (in the sequence of elution from the column) 62.7 mg (36% oftheory, 100% purity) of diastereomer 1 from Example 583 (96% de)Rt=12.53 min and 59.6 mg (34% of theory, 100% purity) of diastereomer 2from Example 584 (96% de) Rt=14.78 min.

[Analytical HPLC: column: Daicel IA-3 3 μm 50×4.6 mm; eluent: 80%isohexane, 20% ethanol; UV detection: 220 nm].

Example 583N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[trans-3-hydroxy-4-methoxypyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

LC-MS (Method 3): R_(t)=1.96 min; MS (ESIpos): m/z=557 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.55 (d, 1H), 8.80 (s, 1H), 8.29 (d,1H), 7.51-7.61 (m, 2H), 6.80 (br t, 1H), 5.30-5.37 (m, 0.45H), 5.22-5.30(m, 0.55H), 4.33-4.44 (m, 1H), 4.22-4.31 (m, 0.45H), 4.11-4.20 (m,0.55H), 3.73-3.82 (m, 0.55H), 3.66-3.71 (m, 0.45H), 3.49-3.64 (m,1.55H), 3.35-3.41 (m, 0.45H), 3.26 (br d, 3.45H), 3.15-3.22 (m, 1H),3.06-3.13 (m, 0.55H), 1.15-1.27 (m, 1H), 0.49-0.69 (m, 3H), 0.29-0.37(m, 1H).

Example 584 N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[trans-3-hydroxy-4-methoxypyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2)

LC-MS (Method 3): R_(t)=1.96 min; MS (ESIpos): m/z=557 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.56 (d, 1H), 8.80 (s, 1H), 8.29 (d,1H), 7.52-7.60 (m, 2H), 6.80 (br t, 1H), 5.23-5.39 (m, 1H), 4.33-4.43(m, 1H), 4.25-4.30 (m, 0.45H), 4.14 (br s, 0.55H), 3.75-3.82 (m, 0.55H),3.66-3.71 (m, 0.45H), 3.50-3.64 (m, 1.55H), 3.35-3.41 (m, 0.45H), 3.26(br d, 3.45H), 3.19 (br d, 1H), 3.06-3.14 (m, 0.55H), 1.16-1.25 (m, 1H),0.50-0.69 (m, 3H), 0.31-0.37 (m, 1H).

Example 585N-(2,6-Dichlorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP3, 60.0 mg (120 μmol) of the compound from Example 160Bwere reacted with 20.2 mg (144 μmol) of (3R,4R)-pyrrolidine-3,4-diolhydrochloride and 73 μl (420 μmol) of DIPEA in 540 μl of DMF. The crudeproduct was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 53.3 mg (76% of theory, 98%purity) of the title compound were obtained.

LC-MS (Method 1): R_(t)=0.91 min; MS (ESIpos): m/z=565 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=11.95 (s, 1H), 8.89 (s, 1H), 8.34 (d,1H), 7.48-7.65 (m, 4H), 7.38 (t, 1H), 6.81 (d, 1H), 5.25 (d, 1H), 5.16(d, 1H), 4.06 (br s, 1H), 3.94 (br s, 1H), 3.63 (br dd, 1H), 3.33-3.39(m, 1H), 3.23-3.29 (m, 1H), 3.09 (br d, 1H).

Example 586N-[1,1,1,4,4,4-Hexafluorobutan-2-yl]-4-oxo-7-(2-oxoimidazolidin-1-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Racemate)

According to GP1, 40.0 mg (89.4 μmol, 90% purity) of the compound fromExample 113A were reacted with 27.2 mg (125 μmol) of1,1,1,4,4,4-hexafluorobutan-2-amine hydrochloride in the presence of40.8 mg (107 μmol) of HATU and 47 μl (270 μmol) of DIPEA in 330 μl ofDMF. The crude product was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 33.3 mg (66% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.90 min; MS (ESIpos): m/z=568 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.47 (d, 1H), 9.02 (s, 1H), 8.55 (d,1H), 8.44 (d, 1H), 7.67 (s, 1H), 7.54-7.61 (m, 2H), 5.21-5.32 (m, 1H),3.60 (t, 2H), 3.33-3.38 (m, 2H), 3.07-3.20 (dt, 1H), 2.90-3.03 (m, 1H).

25.4 mg of the title compound (racemate) were separated into theenantiomers by chiral HPLC (preparative HPLC: column: Daicel ChiralpakIF 5 m 250×20 mm; eluent: 80% n-heptane, 20% ethanol; temperature: 25°C.; flow rate: 15 ml/min; UV detection: 220 nm).

This gave (in the sequence of elution from the column) 10.0 mg (20% oftheory, 100% purity) of enantiomer 1 from Example 587 (99% ee) Rt=12.96min and 9.00 mg (18% of theory, 100% purity) of enantiomer 2 fromExample 588 (98% ee) Rt=14.19 min.

[Analytical HPLC: column: Daicel Chiralpak IF 5 m 250×4.6 mm; eluent:80% isohexane, 20% ethanol; temperature: 30° C.; flow rate: 1.0 ml/min;UV detection: 220 nm]

Example 587N-[1,1,1,4,4,4-Hexafluorobutan-2-yl]-4-oxo-7-(2-oxoimidazolidin-1-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Enantiomer 1)

LC-MS (Method 3): R_(t)=1.91 min; MS (ESIpos): m/z=568 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.47 (d, 1H), 9.02 (s, 1H), 8.55 (d,1H), 8.44 (d, 1H), 7.67 (br s, 1H), 7.58 (t, 2H), 5.21-5.33 (m, 1H),3.56-3.63 (m, 2H), 3.32-3.38 (m, 2H), 3.08-3.20 (m, 1H), 2.90-3.03 (m,1H).

Example 588N-[1,1,1,4,4,4-Hexafluorobutan-2-yl]-4-oxo-7-(2-oxoimidazolidin-1-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Enantiomer 2)

LC-MS (Method 3): R_(t)=1.92 min; MS (ESIpos): m/z=568 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.47 (d, 1H), 9.02 (s, 1H), 8.55 (d,1H), 8.44 (d, 1H), 7.67 (s, 1H), 7.54-7.61 (m, 2H), 5.23-5.30 (m, 1H),3.57-3.62 (m, 2H), 3.32-3.37 (m, 2H), 3.09-3.20 (m, 1H), 2.90-3.02 (m,1H).

Example 5897-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP3, 50.0 mg (108 μmol) of the compound from Example 115Awere reacted with 18.1 mg (129 μmol) of (3R,4R)-pyrrolidine-3,4-diolhydrochloride and 66 μl (380 μmol) of DIPEA in 500 μl of DMF. The crudeproduct was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 43.1 mg (75% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.70 min; MS (ESIpos): m/z=531 [M+H]⁺

¹H NMR (500 MHz, DMSO-d₆): δ ppm=10.43 (d, 1H), 8.81 (s, 1H), 8.28 (d,1H), 7.53-7.60 (m, 2H), 6.78 (d, 1H), 5.24 (d, 1H), 5.14 (d, 1H),4.69-4.78 (m, 1H), 4.05 (br s, 1H), 3.93 (br s, 1H), 3.62 (br dd, 1H),3.33-3.37 (m, 1H), 3.25 (br dd, 1H), 3.07 (br d, 1H), 1.83-1.92 (m, 1H),1.59-1.69 (m, 1H), 0.97 (t, 3H).

Example 590N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP3, 50.0 mg (105 μmol) of the compound from Example 126Awere reacted with 17.6 mg (126 μmol) of (3R,4R)-pyrrolidine-3,4-diolhydrochloride and 64 μl (370 μmol) of DIPEA in 500 μl of DMF. The crudeproduct was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 45.5 mg (80% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.73 min; MS (ESIpos): m/z=543 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.57 (d, 1H), 8.80 (s, 1H), 8.28 (d,1H), 7.52-7.60 (m, 2H), 6.78 (d, 1H), 5.23 (d, 1H), 5.14 (d, 1H),4.33-4.44 (m, 1H), 4.04-4.07 (m, 1H), 3.93 (br s, 1H), 3.62 (br dd, 1H),3.32-3.37 (m, 1H), 3.25 (br dd, 1H), 3.07 (br d, 1H), 1.19-1.24 (m, 1H),0.50-0.69 (m, 3H), 0.30-0.38 (m, 1H).

Example 5917-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-N-(1,1,3,3,3-hexafluoro-2-methylpropan-2-yl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP3, 25.0 mg (48.3 μmol) of the compound from Example 159Awere reacted with 8.09 mg (57.9 μmol) of (3R,4R)-pyrrolidine-3,4-diolhydrochloride and 29 μl (170 μmol) of DIPEA in 220 μl of DMF. The crudeproduct was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 25.7 mg (91% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.91 min; MS (ESIpos): m/z=585 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=11.61 (s, 1H), 8.84 (s, 1H), 8.30 (d,1H), 7.54-7.61 (m, 2H), 6.80 (d, 1H), 5.24 (d, 1H), 5.15 (d, 1H),4.03-4.07 (m, 1H), 3.90-3.95 (m, 1H), 3.62 (dd, 1H), 3.33-3.39 (m, 1H),3.25 (dd, 1H), 3.07 (d, 1H), 2.06 (br s, 3H).

Example 592N-(2,6-Dichlorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 60.0 mg (120 μmol) of the compound from Example 160Bwere reacted with 19.9 mg (144 μmol) of (4S)-4-hydroxypyrrolidin-2-onehydrochloride in the presence of 24.9 mg (180 μmol) of potassiumcarbonate, 5.40 mg (24.1 μmol) of palladium acetate and 13.9 mg (24.1μmol) of Xantphos in 1.1 ml of 1,4-dioxane. The crude product waspurified by means of preparative HPLC (acetonitrile/water/0.1% formicacid). The substance was recrystallized from acetonitrile, filtered offwith suction, washed with a little acetonitrile and dried. The substancewas isolated with impurities and was further purified subsequently bymeans of normal phase chromatography (eluent: cyclohexane-ethyl acetategradient). 6.20 mg (9% of theory, 100% purity) of the title compoundwere obtained.

LC-MS (Method 1): R_(t)=1.00 min; MS (ESIpos): m/z=563 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=11.60 (s, 1H), 9.16 (s, 1H), 8.78 (d,1H), 8.57 (d, 1H), 7.58-7.66 (m, 4H), 7.39 (t, 1H), 5.35 (br s, 1H),4.22-4.36 (m, 1H), 3.71 (dd, 1H), 3.49 (d, 1H), 2.96 (dd, 1H).

Example 593 Methyl4-{6-[(2,6-dichlorophenyl)carbamoyl]-5-oxo-8-(2,4,6-trifluorophenyl)-5,8-dihydro-1,8-naphthyridin-2-yl}piperazine-1-carboxylate

According to GP3, 60.0 mg (120 μmol) of the compound from Example 160Bwere reacted with 20.8 mg (144 μmol) of methyl piperazine-1-carboxylateand 73 μl (420 μmol) of DIPEA in 540 μl of DMF. The crude product waspurified by means of preparative HPLC (acetonitrile/water/0.1% formicacid). 40.3 mg (55% of theory, 100% purity) of the title compound wereobtained.

LC-MS (Method 3): R_(t)=2.14 min; MS (ESIpos): m/z=606 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=11.86 (s, 1H), 8.93 (s, 1H), 8.39 (d,1H), 7.54-7.61 (m, 4H), 7.38 (t, 1H), 7.16 (d, 1H), 3.61 (s, 3H),3.50-3.58 (m, 4H), 3.38-3.46 (m, 4H).

Example 594 Methyl4-[6-{[(1R)-1-cyclopropyl-2,2,2-trifluoroethyl]carbamoyl}-5-oxo-8-(2,4,6-trifluorophenyl)-5,8-dihydro-1,8-naphthyridin-2-yl]piperazine-1-carboxylate

According to GP1, 70.0 mg (151 μmol) of the compound from Example 157Awere reacted with 31.9 mg (182 μmol) of(1R)-1-cyclopropyl-2,2,2-trifluoroethanamine hydrochloride in thepresence of 69.1 mg (182 μmol) of HATU and 110 μl (610 μmol) of DIPEA in580 μl of DMF. The crude product was purified by means of preparativeHPLC (acetonitrile/water/0.1% formic acid). 50.9 mg (58% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=2.13 min; MS (ESIpos): m/z=584 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.49 (d, 1H), 8.83 (s, 1H), 8.33 (d,1H), 7.53-7.60 (m, 2H), 7.14 (d, 1H), 4.33-4.43 (m, 1H), 3.61 (s, 3H),3.50-3.57 (m, 4H), 3.36-3.43 (m, 4H), 1.16-1.25 (m, 1H), 0.50-0.69 (m,3H), 0.31-0.37 (m, 1H).

Example 595 Methyl4-[5-oxo-6-{[(2S)-1,1,1-trifluorobutan-2-yl]carbamoyl}-8-(2,4,6-trifluorophenyl)-5,8-dihydro-1,8-naphthyridin-2-yl]piperazine-1-carboxylate

According to GP1, 70.0 mg (151 μmol) of the compound from Example 157Awere reacted with 29.7 mg (182 μmol) of(2S)-1,1,1-trifluorobutan-2-amine hydrochloride in the presence of 69.1mg (182 μmol) of HATU and 79 μl (450 μmol) of DIPEA in 580 μl of DMF.The crude product was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 46.5 mg (54% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=2.11 min; MS (ESIpos): m/z=572 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.36 (d, 1H), 8.84 (s, 1H), 8.33 (d,1H), 7.57 (t, 2H), 7.14 (d, 1H), 4.69-4.79 (m, 1H), 3.61 (s, 3H),3.48-3.58 (m, 4H), 3.36-3.44 (m, 4H), 1.83-1.92 (m, 1H), 1.59-1.69 (m,1H), 0.97 (t, 3H).

Example 5964-Oxo-7-(2-oxoimidazolidin-1-yl)-N-[1-(trifluoromethyl)cyclobutyl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 50.0 mg (124 μmol) of the compound from Example 113Awere reacted with 26.1 mg (148 μmol) of1-(trifluoromethyl)cyclobutanamine hydrochloride in the presence of 56.4mg (148 μmol) of HATU and 65 μl (370 μmol) of DIPEA in 480 μl of DMF.The crude product was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 41.6 mg (64% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.97 min; MS (ESIpos): m/z=526 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.31 (s, 1H), 8.94 (s, 1H), 8.55 (d,1H), 8.43 (d, 1H), 7.66 (s, 1H), 7.58 (t, 2H), 3.56-3.63 (m, 2H),3.32-3.38 (m, 2H), 2.54-2.66 (m, 4H), 1.90-2.09 (m, 2H).

Example 597N-(2,6-Dichlorophenyl)-1-(2,4-difluorophenyl)-7-[1-hydroxy-3-azabicyclo[3.1.0]hex-3-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Racemate)

According to GP3, 90.0 mg (187 μmol) of the compound from Example 81Awere reacted with 30.5 mg (225 μmol) of 3-azabicyclo[3.1.0]hexan-1-oland 110 μl (660 μmol) of DIPEA in 900 μl of DMF. The crude product waspurified by means of preparative HPLC (acetonitrile/water/0.1% formicacid). 62.1 mg (61% of theory, 100% purity) of the title compound wereobtained.

LC-MS (Method 3): R_(t)=2.02 min; MS (ESIpos): m/z=543 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=11.99 (s, 1H), 8.69 (s, 1H), 8.34 (d,1H), 7.78-7.89 (m, 1H), 7.54-7.65 (m, 3H), 7.29-7.40 (m, 2H), 6.70-6.83(m, 1H), 5.90-6.13 (m, 1H), 3.79-3.95 (m, 0.50H), 3.37-3.75 (m, 2.50H),3.08-3.23 (m, 1H), 1.52-1.70 (m, 1H), 0.95-1.08 (m, 1H), 0.37-0.50 (m,1H).

Example 5987-(3-Methoxy-3-methylazetidin-1-yl)-4-oxo-N-[(2S)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 24.1 mg (57.5 μmol) of the compound from Example 161Awere reacted with 13.2 mg (69.0 μmol) of(2S)-1,1,1-trifluoro-3,3-dimethylbutan-2-amine hydrochloride in thepresence of 26.3 mg (69.0 μmol) of HATU and 30 μl (170 μmol) of DIPEA in230 μl of DMF. The crude product was purified by means of preparativeHPLC (acetonitrile/water/0.1% formic acid). 23.2 mg (72% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=2.47 min; MS (ESIpos): m/z=557 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.73 (d, 1H), 8.81 (s, 1H), 8.33 (d,1H), 7.54 (t, 2H), 6.64 (d, 1H), 4.62 (quint, 1H), 3.47-4.12 (m, 4H),3.16 (s, 3H), 1.41 (s, 3H), 1.08 (s, 9H).

Example 599N-(1,1,1,3,3,3-Hexafluoropropan-2-yl)-4-oxo-7-(2-oxoimidazolidin-1-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 60.0 mg (119 μmol) of the compound from Example 154Awere reacted with 103 mg (1.19 mmol) of imidazolidin-2-one in thepresence of 24.7 mg (179 μmol) of potassium carbonate, 5.35 mg (23.8μmol) of palladium acetate and 13.8 mg (23.8 μmol) of Xantphos in 1.2 mlof 1,4-dioxane. The crude product was purified by means of preparativeHPLC (acetonitrile/water/0.1% formic acid). 34.4 mg (52% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=2.05 min; MS (ESIpos): m/z=554 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=11.15 (d, 1H), 9.12 (s, 1H), 8.58 (d,1H), 8.46 (d, 1H), 7.69 (s, 1H), 7.59 (t, 2H), 6.33-6.40 (m, 1H),3.57-3.62 (m, 2H), 3.33-3.38 (m, 2H).

Example 600N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[7-hydroxy-5-azaspiro[2.4]hept-5-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP1, 80.0 mg (185 μmol) of the compound from Example 155Awere reacted with 39.1 mg (223 μmol) of(1S)-1-cyclopropyl-2,2,2-trifluoroethanamine hydrochloride in thepresence of 84.6 mg (223 μmol) of HATU and 97 μl (560 μmol) of DIPEA in890 μl of DMF. The crude product was purified by means of preparativeHPLC (acetonitrile/water/0.1% formic acid). 67.6 mg (66% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 4): R_(t)=3.62 min; MS (ESIpos): m/z=553 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.56 (d, 1H), 8.77-8.82 (m, 1H), 8.29(d, 1H), 7.46-7.64 (m, 2H), 6.81 (br d, 0.40H), 6.69 (br d, 0.60H),4.95-5.11 (m, 1H), 4.33-4.43 (m, 1H), 3.59-3.78 (m, 2H), 3.40-3.48 (m,1.60H), 3.13-3.27 (m, 1H), 2.89 (s, 0.40H), 1.16-1.25 (m, 1H), 0.77-0.86(m, 1H), 0.46-0.69 (m, 6H), 0.29-0.38 (m, 1H).

59.0 mg of the title compound (diastereomer mixture) were separated intothe diastereomers by chiral HPLC (preparative HPLC: column: YMCChiralart Amylose SA 5 μm 250×30 mm; eluent: 80% n-heptane, 20% ethanol;temperature: 25° C.; flow rate: 30 ml/min; UV detection: 220 nm).

This gave (in the sequence of elution from the column) 23.0 mg (22% oftheory, 100% purity) of diastereomer 1 from Example 601 (99% de) Rt=9.88min and 22.0 mg (21% of theory, 100% purity) of diastereomer 2 fromExample 602 (99% de) Rt=12.57 min.

[Analytical HPLC: column: YMC Chiralart Amylose SA 5 μm 250×4.6 mm;eluent: 80% isohexane, 20% ethanol; temperature: 30° C.; flow rate: 1.0ml/min; UV detection: 220 nm]

Example 601N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[7-hydroxy-5-azaspiro[2.4]hept-5-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

LC-MS (Method 3): R_(t)=2.08 min; MS (ESIpos): m/z=553 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.56 (d, 1H), 8.77-8.82 (m, 1H), 8.29(d, 1H), 7.46-7.64 (m, 2H), 6.81 (br d, 0.40H), 6.69 (br d, 0.60H), 5.07(br d, 0.40H), 4.98 (br d, 0.60H), 4.33-4.44 (m, 1H), 3.59-3.79 (m, 2H),3.31-3.47 (m, 1.60H), 3.14-3.27 (m, 1H), 2.88 (br d, 0.40H), 1.14-1.28(m, 1H), 0.76-0.88 (m, 1H), 0.46-0.69 (m, 6H), 0.29-0.39 (m, 1H).

Example 602N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[7-hydroxy-5-azaspiro[2.4]hept-5-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2)

LC-MS (Method 3): R_(t)=2.08 min; MS (ESIpos): m/z=553 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.56 (d, 1H), 8.77-8.82 (m, 1H), 8.29(d, 1H), 7.49-7.60 (m, 2H), 6.81 (br d, 0.40H), 6.69 (br d, 0.60H), 5.08(br d, 0.40H), 4.98 (br d, 0.60H), 4.33-4.43 (m, 1H), 3.59-3.79 (m, 2H),3.31-3.49 (m, 1.60H), 3.21 (br dd, 1H), 2.83-2.93 (m, 0.40H), 1.16-1.26(m, 1H), 0.76-0.87 (m, 1H), 0.43-0.71 (m, 6H), 0.29-0.39 (m, 1H).

Example 603 Methyl 4-[6-{[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]carbamoyl}-5-oxo-8-(2,4,6-trifluorophenyl)-5,8-dihydro-1,8-naphthyridin-2-yl]piperazine-1-carboxylate

According to GP1, 70.0 mg (151 μmol) of the compound from Example 157Awere reacted with 31.9 mg (182 μmol) of(1S)-1-cyclopropyl-2,2,2-trifluoroethanamine hydrochloride in thepresence of 69.1 mg (182 μmol) of HATU and 79 μl (450 μmol) of DIPEA in580 μl of DMF. The crude product was purified by means of preparativeHPLC (acetonitrile/water/0.1% formic acid). 47.9 mg (54% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=2.13 min; MS (ESIpos): m/z=584 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.49 (d, 1H), 8.83 (s, 1H), 8.33 (d,1H), 7.53-7.60 (m, 2H), 7.14 (d, 1H), 4.33-4.43 (m, 1H), 3.61 (s, 3H),3.49-3.57 (m, 4H), 3.36-3.44 (m, 4H), 1.16-1.25 (m, 1H), 0.50-0.69 (m,3H), 0.30-0.38 (m, 1H).

Example 604N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-4-oxo-7-(2-oxotetrahydropyrimidin-1(2H)-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 60.0 mg (126 μmol) of the compound from Example 126Awere reacted with 126 mg (1.26 mmol) of tetrahydropyrimidin-2(1H)-one inthe presence of 26.1 mg (189 μmol) of potassium carbonate, 5.66 mg (25.2μmol) of palladium acetate and 14.6 mg (25.2 μmol) of Xantphos in 1.2 mlof 1,4-dioxane. The crude product was purified by means of preparativeHPLC (acetonitrile/water/0.1% formic acid). 46.0 mg (68% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.94 min; MS (ESIpos): m/z=540 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.33 (d, 1H), 9.01 (s, 1H), 8.52 (d,1H), 8.30 (d, 1H), 7.60 (t, 2H), 7.38-7.41 (m, 1H), 4.35-4.45 (m, 1H),3.50 (br t, 2H), 3.15 (td, 2H), 1.80-1.88 (m, 2H), 1.19-1.27 (m, 1H),0.52-0.70 (m, 3H), 0.31-0.38 (m, 1H).

Example 605N-[(1R)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-(3-methoxy-3-methylazetidin-1-yl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 24.0 mg (57.2 μmol) of the compound from Example 161Awere reacted with 12.1 mg (68.7 μmol) of(1R)-1-cyclopropyl-2,2,2-trifluoroethanamine hydrochloride in thepresence of 26.1 mg (68.7 μmol) of HATU and 30 μl (170 μmol) of DIPEA in230 μl of DMF. The crude product was purified by means of preparativeHPLC (acetonitrile/water/0.1% formic acid). 23.9 mg (77% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=2.32 min; MS (ESIpos): m/z=541 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.52 (d, 1H), 8.80 (s, 1H), 8.30 (d,1H), 7.50-7.58 (m, 2H), 6.64 (d, 1H), 4.33-4.43 (m, 1H), 3.50-4.11 (m,3H), 3.16 (s, 3H), 1.41 (s, 3H), 1.16-1.25 (m, 1H), 0.49-0.69 (m, 3H),0.30-0.37 (m, 1H).

Example 606N-[1,1,1,4,4,4-Hexafluorobutan-2-yl]-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP1, 40.0 mg (95.4 μmol) of the compound from Example 117Awere reacted with 29.1 mg (134 μmol) of1,1,1,4,4,4-hexafluorobutan-2-amine hydrochloride in the presence of43.5 mg (114 μmol) of HATU and 50 μl (290 μmol) of DIPEA in 350 μl ofDMF. The crude product was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 36.5 mg (66% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.00 min; MS (ESIpos): m/z=583 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.37 (d, 1H), 9.09 (s, 1H), 8.71 (d,1H), 8.55 (d, 1H), 7.58-7.66 (m, 2H), 5.21-5.37 (m, 2H), 4.29 (br s,1H), 3.69 (dd, 1H), 3.47 (d, 1H), 3.11-3.22 (m, 1H), 2.90-3.03 (m, 2H),2.38 (br d, 1H).

36.0 mg of the title compound (diastereomer mixture) were separated intothe diastereomers by chiral HPLC (preparative HPLC: column: DaicelChiralcel OX-H 5 μm 250×20 mm; eluent: 80% n-heptane, 20% isopropanol;temperature: 23° C.; flow rate: 20 ml/min; UV detection: 220 nm).

This gave (in the sequence of elution from the column) 10.50 mg (19% oftheory, 100% purity) of diastereomer 1 from Example 607 (99% de) Rt=6.32min and 6.90 mg (12% of theory, 100% purity) of diastereomer 2 fromExample 608 (94% de) Rt=7.62 min.

[Analytical HPLC: column: Daicel OX-3 3 μm 50×4.6 mm; eluent: 80%isohexane, 20% isopropanol; UV detection: 220 nm].

Example 607N-[1,1,1,1,4,4,4-Hexafluorobutan-2-yl]-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

LC-MS (Method 3): R_(t)=1.86 min; MS (ESIpos): m/z=583 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.37 (d, 1H), 9.09 (s, 1H), 8.71 (d,1H), 8.54 (d, 1H), 7.58-7.66 (m, 2H), 5.22-5.34 (m, 1H), 4.29 (br t,1H), 3.69 (dd, 1H), 3.44-3.52 (m, 2H), 3.10-3.23 (m, 1H), 2.90-3.01 (m,2H), 2.38 (d, 1H).

Example 608N-[1,1,1,4,4,4-Hexafluorobutan-2-yl]-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2)

LC-MS (Method 3): R_(t)=1.85 min; MS (ESIpos): m/z=583 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.37 (d, 1H), 9.09 (s, 1H), 8.71 (d,1H), 8.55 (d, 1H), 7.57-7.66 (m, 2H), 5.21-5.34 (m, 1H), 4.27-4.31 (m,1H), 3.69 (dd, 1H), 3.11-3.22 (m, 1H), 2.91-3.02 (m, 2H), 2.38 (br d,1H).

Example 6094-Oxo-7-(2-oxoimidazolidin-1-yl)-N-[1-(trifluoromethoxy)butan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Racemate)

According to GP1, 300 mg (742 μmol) of the compound from Example 113Awere reacted with 201 mg (1.04 mmol) of1-(trifluoromethoxy)butan-2-amine hydrochloride in the presence of 339mg (890 μmol) of HATU and 390 μl (2.20 mmol) of DIPEA in 2.8 ml of DMF.The crude product was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 224 mg (52% of theory, 94%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.92 min; MS (ESIpos): m/z=544 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=9.89 (br d, 1H), 8.92 (s, 1H), 8.55 (d,1H), 8.42 (d, 1H), 7.65 (s, 1H), 7.53-7.63 (m, 2H), 4.15-4.25 (m, 3H),3.54-3.64 (m, 2H), 3.32-3.38 (m, 2H), 1.55-1.74 (m, 2H), 0.95 (t, 3H).

216 mg of the title compound (racemate) were separated into theenantiomers by chiral HPLC (preparative HPLC: column: YMC ChiralartCellulose SB 5 m 250×20 mm; eluent: 70% n-heptane, 30% isopropanol;temperature: 30° C.; flow rate: 15 ml/min; UV detection: 220 nm).

This gave (in the sequence of elution from the column) 91.0 mg (21% oftheory, 100% purity) of enantiomer 1 from Example 610 (99% ee) Rt=12.46min and 88.0 mg (20% of theory, 100% purity) of enantiomer 2 fromExample 611 (98% ee) Rt=14.51 min.

[Analytical HPLC: column: YMC Chiralart Amylose SB 5 m 250×4.6 mm;eluent: 70% isohexane, 30% isopropanol; temperature: 40° C.; flow rate:1.0 ml/min; UV detection: 220 nm]

Example 6104-Oxo-7-(2-oxoimidazolidin-1-yl)-N-[1-(trifluoromethoxy)butan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Enantiomer 1)

LC-MS (Method 3): R_(t)=1.94 min; MS (ESIpos): m/z=544 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=9.89 (br d, 1H), 8.92 (s, 1H), 8.55 (d,1H), 8.42 (d, 1H), 7.65 (s, 1H), 7.54-7.61 (m, 2H), 4.15-4.24 (m, 3H),3.55-3.63 (m, 2H), 3.32-3.38 (m, 2H), 1.55-1.74 (m, 2H), 0.95 (t, 3H).

Example 6114-Oxo-7-(2-oxoimidazolidin-1-yl)-N-[1-(trifluoromethoxy)butan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Enantiomer 2)

LC-MS (Method 3): R_(t)=1.94 min; MS (ESIpos): m/z=544 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=9.89 (br d, 1H), 8.92 (s, 1H), 8.55 (d,1H), 8.42 (d, 1H), 7.65 (s, 1H), 7.53-7.62 (m, 2H), 4.15-4.24 (m, 3H),3.55-3.63 (m, 2H), 3.32-3.38 (m, 2H), 1.54-1.74 (m, 2H), 0.95 (t, 3H).

Example 6127-[(3R,4S)-3,4-Dihydroxypyrrolidin-1-yl]-4-oxo-N-(4,4,4-trifluoro-2-methylbutan-2-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 60.0 mg (142 μmol) of the compound from Example 156Awere reacted with 30.3 mg (171 μmol) of4,4,4-trifluoro-2-methylbutan-2-amine hydrochloride in the presence of65.0 mg (171 μmol) of HATU and 99 μl (570 μmol) of DIPEA in 1.2 ml ofDMF. The crude product was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 56.0 mg (72% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.75 min; MS (ESIpos): m/z=545 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.16 (s, 1H), 8.69 (s, 1H), 8.25 (d,1H), 7.52-7.60 (m, 2H), 6.73 (d, 1H), 5.03 (d, 1H), 4.93 (d, 1H),4.09-4.17 (m, 1H), 3.99-4.07 (m, 1H), 3.55-3.63 (m, 1H), 3.19-3.30 (m,2H), 2.89-3.04 (m, 3H), 1.48 (s, 6H).

Example 613N-(2,6-Dichlorophenyl)-4-oxo-7-(2-oxoimidazolidin-1-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 60.0 mg (120 μmol) of the compound from Example 160Bwere reacted with 147 mg (1.20 mmol) of imidazolidin-2-one hydrochloridein the presence of 24.9 mg (180 μmol) of potassium carbonate, 5.40 mg(24.1 μmol) of palladium acetate and 13.9 mg (24.1 μmol) of Xantphos in1.1 ml of 1,4-dioxane. The crude product was purified by means ofpreparative HPLC (acetonitrile/water/0.1% formic acid). The substancewas isolated with impurities and was further recrystallized fromacetonitrile, filtered off with suction, washed with a littleacetonitrile and dried. 38.5 mg (58% of theory, 100% purity) of thetitle compound were obtained.

LC-MS (Method 3): R_(t)=1.95 min; MS (ESIpos): m/z=548 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=11.70 (s, 1H), 9.08 (s, 1H), 8.62 (d,1H), 8.47 (d, 1H), 7.68 (s, 1H), 7.54-7.63 (m, 4H), 7.39 (t, 1H),3.57-3.65 (m, 2H), 3.33-3.39 (m, 2H).

Example 614N-(1,1-Difluoro-2-methylpropan-2-yl)-4-oxo-7-(2-oxoimidazolidin-1-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 50.0 mg (124 μmol) of the compound from Example 113Awere reacted with 25.2 mg (173 μmol) of1,1-difluoro-2-methylpropan-2-amine hydrochloride in the presence of56.4 mg (148 μmol) of HATU and 65 μl (370 μmol) of DIPEA in 460 μl ofDMF. The crude product was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 34.9 mg (57% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.86 min; MS (ESIpos): m/z=496 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.12 (s, 1H), 8.91 (s, 1H), 8.55 (d,1H), 8.42 (d, 1H), 7.65 (s, 1H), 7.53-7.61 (m, 2H), 6.43 (t, 1H),3.53-3.65 (m, 2H), 3.32-3.38 (m, 2H), 1.45 (s, 6H).

Example 615 N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[trans-3,4-dihydroxypiperidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP3, 150 mg (315 μmol) of the compound from Example 126Awere reacted with 58.1 mg (378 μmol) of piperidine-3,4-diolhydrochloride and 160 μl (950 μmol) of DIPEA in 1.3 ml of DMF. The crudeproduct was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 153 mg (87% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 4): R_(t)=2.95 min; MS (ESIpos): m/z=557 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.53 (d, 1H), 8.80 (s, 1H), 8.22-8.28(m, 1H), 7.52-7.60 (m, 2H), 7.12 (d, 1H), 4.98 (br s, 1H), 4.86 (br s,1H), 4.33-4.43 (m, 1H), 3.75-3.87 (m, 1H), 3.56-3.75 (m, 1H), 3.39-3.47(m, 1H), 3.10-3.27 (m, 3H), 1.72-1.82 (m, 1H), 1.16-1.27 (m, 2H),0.49-0.69 (m, 3H), 0.31-0.37 (m, 1H).

142 mg of the title compound (diastereomer mixture) were separated intothe diastereomers by chiral HPLC (preparative SFC: column: Chiralpak AD250×20 mm; eluent: 85% carbon dioxide, 15% ethanol; temperature: 40° C.;flow rate: 80 ml/min; UV detection: 210 nm).

This gave (in the sequence of elution from the column) 63.80 mg (15% oftheory, 100% purity) of diastereomer 1 from Example 616 (99% de) Rt=7.56min and 62.10 mg (18% of theory, 100% purity) of diastereomer 2 fromExample 617 (96% de) Rt=9.25 min.

[Analytical SFC: column: AD; eluent: 80% carbon dioxide, 20% ethanol;flow rate: 3.0 ml/min; UV detection: 210 nm].

Example 616N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[trans-3,4-dihydroxypiperidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

LC-MS (Method 1): R_(t)=0.96 min; MS (ESIpos): m/z=557 [M+H]⁺

¹H NMR (600 MHz, DMSO-d₆): δ ppm=10.54 (d, 1H), 8.80 (s, 1H), 8.26 (d,1H), 7.54-7.60 (m, 2H), 7.12 (d, 1H), 4.96-5.03 (m, 1H), 4.88 (d, 1H),4.34-4.41 (m, 1H), 3.76-3.84 (m, 1H), 3.52-3.74 (m, 1H), 3.39-3.46 (m,1H), 3.05-3.29 (m, 2H), 1.71-1.82 (m, 1H), 1.17-1.26 (m, 2H), 0.63-0.68(m, 1H), 0.51-0.60 (m, 2H), 0.31-0.35 (m, 1H).

Example 617 N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[trans-3,4-dihydroxypiperidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2)

LC-MS (Method 1): R_(t)=0.96 min; MS (ESIpos): m/z=557 [M+H]⁺

¹H NMR (600 MHz, DMSO-d₆): δ ppm=10.54 (d, 1H), 8.80 (s, 1H), 8.26 (d,1H), 7.54-7.60 (m, 2H), 7.12 (d, 1H), 5.00 (br d, 1H), 4.88 (d, 1H),4.34-4.41 (m, 1H), 3.77-3.84 (m, 1H), 3.68 (br s, 1H), 3.38-3.48 (m,2H), 3.18-3.26 (m, 2H), 1.76 (br s, 1H), 1.21-1.28 (m, 1H), 1.16-1.26(m, 1H), 0.63-0.68 (m, 1H), 0.51-0.60 (m, 2H), 0.33 (br dd, 1H).

Example 6181-(2,6-Difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

To a solution of 115 mg (155 μmol) of the compound from Example 165A in1.3 ml of THF were added 350 μl (1.0 M in THF, 350 μmol) oftetra-n-butylammonium fluoride, and the reaction mixture was stirred atroom temperature for 2 h. The solvent was removed under reduced pressureand the residue was purified by means of normal phase chromatography(ethyl acetate-cyclohexane gradient). The substance was isolated withimpurities and was purified further by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 26 mg (33% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.63 min; MS (ESIpos): m/z=513 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.45 (d, 1H), 8.75 (s, 1H), 8.28 (d,1H), 7.67-7.75 (m, 1H), 7.42 (t, 2H), 6.78 (d, 1H), 5.22 (d, 1H), 5.13(d, 1H), 4.68-4.79 (m, 1H), 4.04 (br s, 1H), 3.89 (br s, 1H), 3.57-3.64(m, 1H), 3.32-3.37 (m, 1H), 3.19 (dd, 1H), 3.02 (d, 1H), 1.83-1.93 (m,1H), 1.59-1.70 (m, 1H), 0.97 (t, 3H).

Example 6197-[7-Hydroxy-5-azaspiro[2.4]hept-5-yl]-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP1, 80.0 mg (185 μmol) of the compound from Example 155Awere reacted with 36.4 mg (223 μmol) of(2S)-1,1,1-trifluorobutan-2-amine hydrochloride in the presence of 84.6mg (223 μmol) of HATU and 97 μl (560 μmol) of DIPEA in 890 μl of DMF.The crude product was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 90.2 mg (90% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 4): R_(t)=3.57 min; MS (ESIpos): m/z=541 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.43 (d, 1H), 8.77-8.82 (m, 1H), 8.28(d, 1H), 7.49-7.61 (m, 2H), 6.80 (br d, 0.40H), 6.69 (d, 0.60H),5.04-5.11 (m, 0.40H), 4.95-5.02 (m, 0.60H), 4.68-4.78 (m, 1H), 3.61-3.78(m, 2H), 3.34-3.49 (m, 1.60H), 3.14-3.26 (m, 1H), 2.84-2.92 (m, 0.40H),1.83-1.92 (m, 1H), 1.58-1.70 (m, 1H), 0.97 (t, 3H), 0.77-0.86 (m, 1H),0.44-0.63 (m, 3H).

78.7 mg of the title compound (diastereomer mixture) were separated intothe diastereomers by chiral HPLC (preparative HPLC: column: DaicelChiralpak IA 5 m 250×20 mm; eluent: 80% n-heptane, 20% ethanol;temperature: 25° C.; flow rate: 15 ml/min; UV detection: 210 nm).

This gave (in the sequence of elution from the column) 33.4 mg (33% oftheory, 100% purity) of diastereomer 1 from Example 620 (99% de) Rt=8.04min and 34.5 mg (34% of theory, 100% purity) of diastereomer 2 fromExample 621 (98% de) Rt=9.82 min.

[Analytical HPLC: column: Daicel IA-3 3 m 50×4.6 mm; eluent: 80%isohexane, 20% ethanol; UV detection: 220 nm].

Example 6207-[7-Hydroxy-5-azaspiro[2.4]hept-5-yl]-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

LC-MS (Method 1): R_(t)=1.10 min; MS (ESIpos): m/z=541 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.43 (d, 1H), 8.78-8.83 (m, 1H), 8.28(d, 1H), 7.49-7.61 (m, 2H), 6.81 (br d, 0.40H), 6.69 (br d, 0.60H),4.93-5.13 (m, 1H), 4.68-4.79 (m, 1H), 3.60-3.78 (m, 2H), 3.32-3.48 (m,1.60H), 3.14-3.27 (m, 1H), 2.88 (br d, 0.40H), 1.83-1.93 (m, 1H),1.58-1.70 (m, 1H), 0.97 (t, 3H), 0.76-0.88 (m, 1H), 0.44-0.63 (m, 3H).

Example 6217-[7-Hydroxy-5-azaspiro[2.4]hept-5-yl]-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2)

LC-MS (Method 1): R_(t)=1.10 min; MS (ESIpos): m/z=541 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.43 (d, 1H), 8.78-8.83 (m, 1H), 8.28(d, 1H), 7.49-7.61 (m, 2H), 6.81 (br d, 0.40H), 6.69 (br d, 0.60H),4.92-5.19 (m, 1H), 4.68-4.79 (m, 1H), 3.59-3.78 (m, 2H), 3.33-3.48 (m,1.60H), 3.14-3.27 (m, 1H), 2.88 (br d, 0.40H), 1.83-1.93 (m, 1H),1.58-1.70 (m, 1H), 0.97 (t, 3H), 0.76-0.88 (m, 1H), 0.44-0.63 (m, 3H).

Example 6221-(2,4-Difluorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[3,3,4,4,4-pentafluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP1, 150 mg (374 μmol) of the compound from Example 63Awere reacted with 89.5 mg (449 μmol) of3,3,4,4,4-pentafluorobutan-2-amine hydrochloride in the presence of 171mg (449 μmol) of HATU and 260 μl (1.50 mmol) of DIPEA in 1.5 ml of DMF.The crude product was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 177 mg (87% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.03 min; MS (ESIpos): m/z=547 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.35 (br d, 1H), 8.85 (d, 1H), 8.70(d, 1H), 8.52 (dd, 1H), 7.81-7.93 (m, 1H), 7.63 (br t, 1H), 7.37 (br t,1H), 5.28-5.36 (m, 1H), 4.98-5.11 (m, 1H), 4.26-4.31 (m, 1H), 3.62-3.71(m, 1H), 3.42-3.51 (m, 1H), 2.89-2.99 (m, 1H), 2.32-2.41 (m, 1H), 1.41(d, 3H).

167 mg of the title compound (diastereomer mixture) were separated intothe diastereomers by chiral HPLC (preparative HPLC: column: ChiralpakAD-H 5 μm 250×30 mm; eluent: 80% n-heptane, 20% isopropanol;temperature: 23° C.; flow rate: 50 ml/min; UV detection: 220 nm).

This gave (in the sequence of elution from the column) 74.1 mg ofdiastereomer 1 (99% de) Rt=6.33 min and 71.3 mg of diastereomer 2 (95%de) Rt=9.54 min.

[Analytical HPLC: column: Daicel AD-3 3 μm 50×4.6 mm; eluent: 80%isohexane, 20% isopropanol; UV detection: 220 nm].

Diastereomer 1 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125*40 mm, solvent: acetonitrile,water, 0.1% formic acid), and 60.3 mg (30% of theory, 100% purity) ofthe title compound from Example 623 were obtained.

Diastereomer 2 was additionally purified by means of preparative HPLC(column: Chromatorex C18, 10 μm, 125*40 mm, solvent: acetonitrile,water, 0.1% formic acid), and 60.2 mg (30% of theory, 100% purity) ofthe title compound from Example 624 were obtained.

Example 6231-(2,4-Difluorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[3,3,4,4,4-pentafluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 1)

LC-MS (Method 3): R_(t)=1.88 min; MS (ESIpos): m/z=547 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.35 (d, 1H), 8.83-8.87 (m, 1H), 8.70(d, 1H), 8.51 (dd, 1H), 7.80-7.93 (m, 1H), 7.63 (br t, 1H), 7.37 (br t,1H), 5.28-5.37 (m, 1H), 4.98-5.11 (m, 1H), 4.26-4.31 (m, 1H), 3.66 (td,1H), 3.47 (br t, 1H), 2.88-2.99 (m, 1H), 2.32-2.42 (m, 1H), 1.41 (d,3H).

Example 6241-(2,4-Difluorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[3,3,4,4,4-pentafluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer 2)

LC-MS (Method 3): R_(t)=1.88 min; MS (ESIpos): m/z=547 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.35 (br dd, 1H), 8.85 (d, 1H), 8.70(d, 1H), 8.52 (dd, 1H), 7.82-7.92 (m, 1H), 7.62 (br t, 1H), 7.37 (br t,1H), 5.27-5.36 (m, 1H), 4.98-5.12 (m, 1H), 4.26-4.31 (m, 1H), 3.62-3.72(m, 1H), 3.46 (br t, 1H), 2.89-3.00 (m, 1H), 2.37 (br dd, 1H), 1.41 (d,3H).

Example 6257-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-4-oxo-N-[1-(trifluoromethyl)cyclobutyl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 50.0 mg (119 μmol) of the compound from Example 121Awere reacted with 25.0 mg (142 μmol) of1-(trifluoromethyl)cyclobutanamine hydrochloride in the presence of 54.1mg (142 μmol) of HATU and 62 μl (360 μmol) of DIPEA in 460 μl of DMF.The crude product was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 48.7 mg (76% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.73 min; MS (ESIpos): m/z=543 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.54 (s, 1H), 8.75 (s, 1H), 8.27 (d,1H), 7.53-7.60 (m, 2H), 6.77 (d, 1H), 5.10-5.31 (m, 2H), 4.05 (br s,1H), 3.93 (br s, 1H), 3.57-3.64 (m, 1H), 3.33-3.37 (m, 2H), 3.21-3.28(m, 2H), 3.07 (br d, 1H), 2.56-2.65 (m, 2H), 1.90-2.06 (m, 2H).

Example 626N-(Bicyclo[1.1.1]pent-1-yl)-7-[7-hydroxy-5-azaspiro[2.4]hept-5-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Racemate)

According to GP1, 80.0 mg (119 μmol) of the compound from Example 155Awere reacted with 26.6 mg (223 μmol) of bicyclo[1.1.1]pentan-1-aminehydrochloride in the presence of 84.6 mg (223 μmol) of HATU and 97 μl(560 μmol) of DIPEA in 890 μl of DMF. The crude product was purified bymeans of preparative HPLC (acetonitrile/water/0.1% formic acid). 57.8 mg(63% of theory, 100% purity) of the title compound were obtained.

LC-MS (Method 4): R_(t)=3.34 min; MS (ESIpos): m/z=497 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.28 (s, 1H), 8.63-8.68 (m, 1H), 8.25(d, 1H), 7.49-7.61 (m, 2H), 6.78 (br d, 0.40H), 6.66 (br d, 0.60H),5.02-5.11 (m, 0.40H), 4.95-5.02 (m, 0.60H), 3.58-3.78 (m, 2H), 3.33-3.47(m, 2H), 3.11-3.25 (m, 1H), 2.87 (br d, 0.40H), 2.09 (s, 6H), 0.77-0.87(m, 1H), 0.52-0.62 (m, 2H), 0.43-0.52 (m, 1H).

53.4 mg of the title compound (racemate) were separated into theenantiomers by chiral HPLC (preparative HPLC: column: YMC ChiralartAmylose SA 5 m 250×30 mm; eluent: 85% n-heptane, 15% ethanol;temperature: 25° C.; flow rate: 30 ml/min; UV detection: 220 nm).

This gave (in the sequence of elution from the column) 22.0 mg (24% oftheory, 100% purity) of enantiomer 1 from Example 627 (99% ee) Rt=15.56min and 23.0 mg (25% of theory, 100% purity) of enantiomer 2 fromExample 628 (99% ee) Rt=18.15 min.

[Analytical HPLC: column: YMC Chiralart Amylose SA 5 m 250×4.6 mm;eluent: 80% isohexane, 20% ethanol; temperature: 25° C.; flow rate: 1.0ml/min; UV detection: 220 nm]

Example 627N-(Bicyclo[1.1.1]pent-1-yl)-7-[7-hydroxy-5-azaspiro[2.4]hept-5-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Enantiomer 1)

LC-MS (Method 3): R_(t)=1.99 min; MS (ESIpos): m/z=497 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.28 (s, 1H), 8.63-8.68 (m, 1H), 8.25(d, 1H), 7.49-7.61 (m, 2H), 6.77 (br d, 0.40H), 6.66 (br d, 0.60H),5.02-5.09 (m, 0.40H), 4.94-5.02 (m, 0.60H), 3.60-3.77 (m, 2H), 3.31-3.47(m, 1.60H), 3.14-3.25 (m, 1H), 2.87 (d, 0.40H), 2.09 (s, 6H), 0.77-0.87(m, 1H), 0.52-0.62 (m, 2H), 0.43-0.52 (m, 1H).

Example 628N-(Bicyclo[1.1.1]pent-1-yl)-7-[7-hydroxy-5-azaspiro[2.4]hept-5-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Enantiomer 2)

LC-MS (Method 3): R_(t)=1.99 min; MS (ESIpos): m/z=497 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.28 (s, 1H), 8.63-8.68 (m, 1H), 8.25(d, 1H), 7.49-7.61 (m, 2H), 6.78 (br d, 0.40H), 6.66 (br d, 0.60H),5.02-5.09 (m, 0.40H), 4.97 (br d, 0.60H), 3.59-3.78 (m, 2H), 3.32-3.47(m, 1.60H), 3.13-3.25 (m, 1H), 2.87 (br d, 0.40H), 2.09 (s, 6H),0.77-0.87 (m, 1H), 0.44-0.63 (m, 3H).

Example 629N-[(1R)-1-Cyclopropyl-2,2,2-trifluoroethyl]-1-(2,6-difluorophenyl)-4-oxo-7-(2-oxoimidazolidin-1-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 60.0 mg (131 μmol) of the compound from Example 103Awere reacted with 113 mg (1.31 mmol) of imidazolidin-2-one in thepresence of 27.2 mg (197 μmol) of potassium carbonate, 5.88 mg (26.2μmol) of palladium acetate and 15.2 mg (26.2 μmol) of Xantphos in 1.2 mlof 1,4-dioxane. The crude product was purified by means of preparativeHPLC (acetonitrile/water/0.1% formic acid). The substance was isolatedwith impurities and was further recrystallized from acetonitrile,filtered off with suction, washed with a little cold acetonitrile anddried. 39.6 mg (60% of theory, 100% purity) of the title compound wereobtained.

LC-MS (Method 3): R_(t)=1.91 min; MS (ESIpos): m/z=508 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.36 (d, 1H), 8.94 (s, 1H), 8.57 (d,1H), 8.44 (d, 1H), 7.68-7.76 (m, 1H), 7.66 (br s, 1H), 7.43 (t, 2H),4.35-4.45 (m, 1H), 3.50-3.58 (m, 2H), 3.32-3.36 (m, 2H), 1.18-1.27 (m,1H), 0.51-0.70 (m, 3H), 0.32-0.39 (m, 1H).

Example 630N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP3, 60.0 mg (126 μmol) of the compound from Example 126Awere reacted with 21.1 mg (151 μmol) of (3R,4S)-pyrrolidine-3,4-diolhydrochloride and 77 μl (440 μmol) of DIPEA in 600 μl of DMF. The crudeproduct was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 61.2 mg (89% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.77 min; MS (ESIpos): m/z=543 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.56 (d, 1H), 8.80 (s, 1H), 8.28 (d,1H), 7.52-7.60 (m, 2H), 6.76 (d, 1H), 5.04 (d, 1H), 4.94 (d, 1H),4.33-4.43 (m, 1H), 4.10-4.16 (m, 1H), 3.99-4.05 (m, 1H), 3.60 (br dd,1H), 3.20-3.30 (m, 2H), 2.97-3.04 (m, 1H), 1.16-1.25 (m, 1H), 0.49-0.68(m, 3H), 0.29-0.37 (m, 1H).

Example 631N-(2,6-Dichlorophenyl)-1-(2,4-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP3, 40.0 mg (83.2 μmol) of the compound from Example 81Awere reacted with 13.9 mg (99.9 μmol) of (3R,4R)-pyrrolidine-3,4-diolhydrochloride and 51 μl (290 μmol) of DIPEA in 400 μl of DMF. The crudeproduct was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 31.2 mg (68% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.68 min; MS (ESIpos): m/z=547 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=12.04 (s, 1H), 8.68 (s, 1H), 8.34 (d,1H), 7.85 (td, 1H), 7.55-7.61 (m, 2H), 7.30-7.40 (m, 2H), 6.78 (d, 1H),5.07-5.29 (m, 2H), 4.01-4.09 (m, 1H), 3.93 (br s, 1H), 3.57-3.66 (m,1H), 3.16-3.28 (m, 2H), 3.03-3.14 (m, 1H).

Example 6327-[(4S)-4-Hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[1-(2,2,2-trifluoroethyl)cyclopropyl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 23.7 mg (56.4 μmol) of the compound from Example 117Awere reacted with 10.4 mg (59.2 μmol) of1-(2,2,2-trifluoroethyl)cyclopropanamine hydrochloride in the presenceof 25.7 mg (67.7 μmol) of HATU and 39 μl (500 μmol) of DIPEA in 500 μlof DMF. The crude product was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 20.1 mg (66% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.72 min; MS (ESIpos): m/z=541 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=9.99 (s, 1H), 8.97 (s, 1H), 8.67 (d,1H), 8.51 (d, 1H), 7.57-7.65 (m, 2H), 5.32 (d, 1H), 4.26-4.31 (m, 1H),3.68 (dd, 1H), 3.47 (d, 1H), 2.94 (dd, 1H), 2.68 (q, 2H), 2.37 (d, 1H),0.86-0.95 (m, 4H).

Example 633 Methyl4-[6-(bicyclo[1.1.1]pent-1-ylcarbamoyl)-5-oxo-8-(2,4,6-trifluorophenyl)-5,8-dihydro-1,8-naphthyridin-2-yl]piperazine-1-carboxylate

According to GP1, 70.0 mg (151 μmol) of the compound from Example 157Awere reacted with 21.7 mg (182 μmol) of bicyclo[1.1.1]pentan-1-aminehydrochloride in the presence of 69.1 mg (182 μmol) of HATU and 79 μl(450 μmol) of DIPEA in 580 μl of DMF. The crude product was purified bymeans of preparative HPLC (acetonitrile/water/0.1% formic acid). 4.80 mg(6% of theory, 100% purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=2.05 min; MS (ESIpos): m/z=528 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.22 (s, 1H), 8.69 (s, 1H), 8.29 (d,1H), 7.57 (t, 2H), 7.11 (d, 1H), 3.60 (s, 3H), 3.47-3.56 (m, 4H),3.33-3.43 (m, 4H), 2.09 (s, 6H).

Example 634N-(1,1-Difluoro-2-methylpropan-2-yl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 30.0 mg (119 μmol) of the compound from Example 121Awere reacted with 12.4 mg (85.4 μmol) of1,1-difluoro-2-methylpropan-2-amine hydrochloride in the presence of32.5 mg (85.4 μmol) of HATU and 37 μl (210 μmol) of DIPEA in 340 μl ofDMF. The crude product was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 10.3 mg (28% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.61 min; MS (ESIpos): m/z=513 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.32 (s, 1H), 8.71 (s, 1H), 8.26 (d,1H), 7.52-7.60 (m, 2H), 6.76 (d, 1H), 6.43 (t, 1H), 5.23 (d, 1H), 5.13(d, 1H), 4.04 (br s, 1H), 3.88-3.97 (m, 1H), 3.61 (br dd, 1H), 3.32-3.36(m, 1H), 3.21-3.27 (m, 1H), 3.06 (br d, 1H), 1.43 (s, 6H).

Example 6357-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-4-oxo-N-[1-(2,2,2-trifluoroethyl)cyclopropyl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 23.8 mg (56.4 μmol) of the compound from Example 121Awere reacted with 10.4 mg (59.2 μmol) of1-(2,2,2-trifluoroethyl)cyclopropanamine hydrochloride in the presenceof 25.7 mg (67.7 μmol) of HATU and 39 μl (230 μmol) of DIPEA in 500 μlof DMF. The crude product was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 18.9 mg (62% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.53 min; MS (ESIpos): m/z=543 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.25 (s, 1H), 8.70 (s, 1H), 8.24 (d,1H), 7.52-7.59 (m, 2H), 6.75 (d, 1H), 5.22 (d, 1H), 5.13 (d, 1H),4.02-4.06 (m, 1H), 3.90-3.94 (m, 1H), 3.57-3.63 (m, 1H), 3.32-3.35 (m,1H), 3.21-3.27 (m, 1H), 3.06 (br d, 1H), 2.62-2.71 (m, 2H), 0.84-0.93(m, 4H).

Example 6367-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-N-(2,6-dichlorophenyl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP3, 60.0 mg (120 μmol) of the compound from Example 160Bwere reacted with 18.6 mg (144 μmol) of piperazine-1-carboxamide and 73μl (420 μmol) of DIPEA in 540 μl of DMF. The crude product was purifiedby means of preparative HPLC (acetonitrile/water/0.1% formic acid). 44.1mg (62% of theory, 100% purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.73 min; MS (ESIpos): m/z=591 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=11.88 (s, 1H), 8.92 (s, 1H), 8.37 (d,1H), 7.55-7.62 (m, 4H), 7.35-7.41 (m, 1H), 7.18 (d, 1H), 6.04 (s, 2H),3.43-3.54 (m, 4H), 3.32-3.38 (m, 4H).

Example 6371-(2,6-Difluorophenyl)-4-oxo-7-(2-oxoimidazolidin-1-yl)-N-[(2)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 60.0 mg (135 μmol) of the compound from Example 114Awere reacted with 116 mg (1.35 mmol) of imidazolidin-2-one in thepresence of 27.9 mg (202 μmol) of potassium carbonate, 6.04 mg (26.9μmol) of palladium acetate and 15.6 mg (26.9 μmol) of Xantphos in 1.2 mlof 1,4-dioxane. The crude product was purified by means of preparativeHPLC (acetonitrile/water/0.1% formic acid). The substance was isolatedwith impurities and was further recrystallized from acetonitrile,filtered off with suction, washed with a little acetonitrile and dried.33.5 mg (50% of theory, 100% purity) of the title compound wereobtained.

LC-MS (Method 3): R_(t)=1.88 min; MS (ESIpos): m/z=496 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.23 (d, 1H), 8.95 (s, 1H), 8.57 (d,1H), 8.44 (d, 1H), 7.68-7.76 (m, 1H), 7.65 (s, 1H), 7.43 (t, 2H),4.70-4.81 (m, 1H), 3.51-3.57 (m, 2H), 3.32-3.36 (m, 2H), 1.84-1.94 (m,1H), 1.61-1.72 (m, 1H), 0.98 (t, 3H).

Example 6381-(2,6-Difluorophenyl)-4-oxo-7-(2-oxoimidazolidin-1-yl)-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 60.0 mg (135 μmol) of the compound from Example 86Awere reacted with 116 mg (1.35 mmol) of imidazolidin-2-one in thepresence of 27.9 mg (202 μmol) of potassium carbonate, 6.04 mg (26.9μmol) of palladium acetate and 15.6 mg (26.9 μmol) of Xantphos in 1.2 mlof 1,4-dioxane. The crude product was purified by means of preparativeHPLC (acetonitrile/water/0.1% formic acid). The substance was isolatedwith impurities and was further recrystallized from acetonitrile,filtered off with suction, washed with a little cold acetonitrile anddried. 27.5 mg (41% of theory, 100% purity) of the title compound wereobtained.

LC-MS (Method 3): R_(t)=1.88 min; MS (ESIpos): m/z=496 [M+H]⁺

¹H NMR (600 MHz, DMSO-d₆): δ ppm=10.23 (d, 1H), 8.95 (s, 1H), 8.56 (d,1H), 8.44 (d, 1H), 7.69-7.76 (m, 1H), 7.67 (s, 1H), 7.43 (t, 2H),4.72-4.80 (m, 1H), 3.49-3.58 (m, 2H), 3.33-3.35 (m, 1H), 3.31-3.33 (m,1H), 1.86-1.93 (m, 1H), 1.62-1.70 (m, 1H), 0.98 (t, 3H).

Example 6391-(2,4-Difluorophenyl)-7-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP3, 100 mg (224 μmol) of the compound from Example 67Awere reacted with 37.6 mg (269 μmol) of (3R,4S)-pyrrolidine-3,4-diolhydrochloride and 140 μl (790 μmol) of DIPEA in 1.0 ml of DMF. The crudeproduct was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 105 mg (91% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.71 min; MS (ESIpos): m/z=513 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.51 (d, 1H), 8.61 (s, 1H), 8.28 (d,1H), 7.76-7.85 (m, 1H), 7.58 (br t, 1H), 7.33 (br t, 1H), 6.74 (d, 1H),5.02 (br dd, 1H), 4.89-4.96 (m, 1H), 4.67-4.79 (m, 1H), 4.13 (br s, 1H),3.97-4.07 (m, 1H), 3.53-3.65 (m, 1H), 3.16-3.30 (m, 2H), 2.93-3.09 (m,1H), 1.83-1.93 (m, 1H), 1.58-1.69 (m, 1H), 0.97 (t, 3H).

Example 6401-(2,4-Difluorophenyl)-7-[3-hydroxy-2-methyl-5-oxopyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP2, 60.0 mg (135 μmol) of the compound from Example 67Awere reacted with 18.6 mg (162 μmol) of the compound from Example 163Cin the presence of 27.9 mg (202 μmol) of potassium carbonate, 6.04 mg(26.9 μmol) of palladium acetate and 15.6 mg (26.9 μmol) of Xantphos in1.0 ml of 1,4-dioxane. The crude product was purified by means ofpreparative HPLC (acetonitrile/water/0.1% formic acid). The substancewas isolated with impurities and was further purified subsequently bymeans of normal phase chromatography (eluent: cyclohexane-ethyl acetategradient). 21.6 mg (31% of theory, 100% purity) of the title compoundwere obtained.

LC-MS (Method 3): R_(t)=1.90 min; MS (ESIpos): m/z=525 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.17-10.27 (m, 1H), 8.84-8.90 (m, 1H),8.67-8.73 (m, 1H), 8.54 (t, 0.80H), 8.44 (t, 0.20H), 7.84-7.94 (m, 1H),7.59-7.69 (m, 1H), 7.33-7.42 (m, 1H), 5.31-5.41 (m, 1H), 4.71-4.83 (m,1H), 3.88-4.13 (m, 2H), 3.05-3.17 (m, 1H), 2.28 (br dd, 1H), 1.83-1.95(m, 1H), 1.60-1.73 (m, 1H), 0.93-1.05 (m, 5H), 0.84-0.90 (m, 1H).

Example 641N-(Bicyclo[1.1.1]pent-1-yl)-7-(3-methoxy-3-methylazetidin-1-yl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 24.1 mg (57.5 μmol) of the compound from Example 161Awere reacted with 8.26 mg (69.0 μmol) of bicyclo[1.1.1]pentan-1-aminehydrochloride in the presence of 26.3 mg (69.0 μmol) of HATU and 30 μl(170 μmol) of DIPEA in 230 μl of DMF. The crude product was purified bymeans of preparative HPLC (acetonitrile/water/0.1% formic acid). 14.0 mg(50% of theory, 100% purity) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.17 min; MS (ESIpos): m/z=485 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.24 (s, 1H), 8.66 (s, 1H), 8.26 (d,1H), 7.51-7.58 (m, 2H), 6.61 (d, 1H), 3.53-4.02 (m, 4H), 3.15 (s, 3H),2.09 (s, 6H), 1.41 (s, 3H).

Example 642 N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[(3S,4S)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP3, 60.0 mg (126 μmol) of the compound from Example 126Awere reacted with 15.6 mg (151 μmol) of (3S,4S)-pyrrolidine-3,4-diol and55 μl (320 μmol) of DIPEA in 600 μl of DMF. The crude product waspurified by means of preparative HPLC (acetonitrile/water/0.1% formicacid). 60.6 mg (89% of theory, 100% purity) of the title compound wereobtained.

LC-MS (Method 3): R_(t)=1.72 min; MS (ESIpos): m/z=543 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.57 (d, 1H), 8.80 (s, 1H), 8.28 (d,1H), 7.56 (br t, 2H), 6.78 (d, 1H), 5.23 (d, 1H), 5.14 (d, 1H),4.33-4.43 (m, 1H), 4.05 (br s, 1H), 3.93 (br s, 1H), 3.62 (br dd, 1H),3.32-3.38 (m, 1H), 3.25 (br dd, 1H), 3.07 (br d, 1H), 1.16-1.25 (m, 1H),0.50-0.69 (m, 3H), 0.31-0.38 (m, 1H).

Example 6431-(2,6-Dichloro-4-fluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP3, 60.0 mg (121 μmol) of the compound from Example 131Awere reacted with 20.2 mg (145 μmol) of (3R,4R)-pyrrolidine-3,4-diolhydrochloride and 74 μl (420 μmol) of DIPEA in 540 μl of DMF. The crudeproduct was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 56.8 mg (83% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.78 min; MS (ESIpos): m/z=563 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.48 (d, 1H), 8.70 (s, 1H), 8.28 (d,1H), 7.88 (dq, 2H), 6.77 (d, 1H), 5.23 (br d, 1H), 5.15 (br d, 1H),4.68-4.79 (m, 1H), 4.04 (br s, 1H), 3.91 (br s, 1H), 3.61 (br dd, 1H),3.33-3.38 (m, 1H), 3.18 (br dd, 1H), 2.99 (br d, 1H), 1.83-1.93 (m, 1H),1.59-1.71 (m, 1H), 0.98 (t, 3H).

Example 644 N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-1-(2,6-difluorophenyl)-4-oxo-7-(2-oxoimidazolidin-1-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 60.0 mg (131 μmol) of the compound from Example 104Awere reacted with 113 mg (1.31 mmol) of imidazolidin-2-one in thepresence of 27.2 mg (197 μmol) of potassium carbonate, 5.88 mg (26.2μmol) of palladium acetate and 15.2 mg (26.2 μmol) of Xantphos in 1.2 mlof 1,4-dioxane. The crude product was purified by means of preparativeHPLC (acetonitrile/water/0.1% formic acid). The substance was isolatedwith impurities and was further recrystallized from acetonitrile,filtered off with suction, washed with a little cold acetonitrile anddried. 34.7 mg (52% of theory, 100% purity) of the title compound wereobtained.

LC-MS (Method 3): R_(t)=1.91 min; MS (ESIpos): m/z=508 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.36 (d, 1H), 8.94 (s, 1H), 8.57 (d,1H), 8.44 (d, 1H), 7.68-7.76 (m, 1H), 7.65 (s, 1H), 7.43 (t, 2H),4.35-4.45 (m, 1H), 3.50-3.58 (m, 2H), 3.31-3.36 (m, 2H), 1.18-1.27 (m,1H), 0.51-0.70 (m, 3H), 0.32-0.39 (m, 1H).

Example 6451-(2,6-Dichlorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 60.0 mg (125 μmol) of the compound from Example 166Cwere reacted with 15.2 mg (150 μmol) of (4S)-4-hydroxypyrrolidin-2-onein the presence of 26.0 mg (188 μmol) of potassium carbonate, 5.63 mg(25.1 μmol) of palladium acetate and 14.5 mg (25.1 μmol) of Xantphos in1.0 ml of 1,4-dioxane. The crude product was purified by means ofpreparative HPLC (acetonitrile/water/0.1% formic acid). 5.00 mg (7% oftheory, 100% purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.94 min; MS (ESIpos): m/z=543 [M+H]⁺

¹H NMR (500 MHz, DMSO-d₆): δ ppm=10.16 (d, 1H), 8.95 (s, 1H), 8.73 (d,1H), 8.54 (d, 1H), 7.78-7.84 (m, 2H), 7.70 (t, 1H), 5.33 (d, 1H),4.73-4.82 (m, 1H), 4.22-4.26 (m, 1H), 3.56 (dd, 1H), 3.32-3.36 (m, 1H),2.93 (dd, 1H), 2.35 (br d, 1H), 1.86-1.94 (m, 1H), 1.63-1.73 (m, 1H),0.99 (t, 3H).

Example 6461-(2,4-Difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

To a solution of 170 mg (229 μmol) of the compound from 167A in 1.9 mlof THF were added 500 μl (1.0 M in THF, 500 μmol) oftetra-n-butylammonium fluoride, and the reaction mixture was stirred atroom temperature for 2 h. The solvent was removed under reduced pressureand the residue was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 42.0 mg (36% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.65 min; MS (ESIpos): m/z=513 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.52 (d, 1H), 8.61 (s, 1H), 8.28 (d,1H), 7.73-7.85 (m, 1H), 7.52-7.62 (m, 1H), 7.25-7.37 (m, 1H), 6.76 (d,1H), 5.08-5.26 (m, 2H), 4.67-4.79 (m, 1H), 4.04 (br s, 1H), 3.92 (br s,1H), 3.55-3.65 (m, 1H), 3.16-3.28 (m, 2H), 3.00-3.14 (m, 1H), 1.80-1.94(m, 1H), 1.56-1.70 (m, 1H), 0.97 (t, 3H).

Example 647N-[(1R)-1-Cyclopropyl-2,2,2-trifluoroethyl]-1-(2,6-dichloro-4-fluorophenyl)-4-oxo-7-(2-oxoimidazolidin-1-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 60.0 mg (118 μmol) of the compound from Example 130Cwere reacted with 102 mg (1.18 mmol) of imidazolidin-2-one in thepresence of 24.5 mg (177 μmol) of potassium carbonate, 5.30 mg (23.6μmol) of palladium acetate and 13.6 mg (23.6 μmol) of Xantphos in 1.1 mlof 1,4-dioxane. The crude product was purified by means of preparativeHPLC (acetonitrile/water/0.1% formic acid). The substance was isolatedwith impurities and was further recrystallized from acetonitrile,filtered off with suction, washed with a little acetonitrile and dried.33.9 mg (51% of theory, 100% purity) of the title compound wereobtained.

LC-MS (Method 3): R_(t)=2.05 min; MS (ESIpos): m/z=558 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.39 (d, 1H), 8.91 (s, 1H), 8.57 (d,1H), 8.44 (d, 1H), 7.89 (d, 2H), 7.66 (s, 1H), 4.34-4.44 (m, 1H),3.46-3.56 (m, 2H), 3.32-3.37 (m, 2H), 1.18-1.27 (m, 1H), 0.52-0.70 (m,3H), 0.32-0.39 (m, 1H).

Example 6481-(2,6-Difluorophenyl)-7-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP3, 40.0 mg (89.7 μmol) of the compound from Example 86Awere reacted with 15.0 mg (108 μmol) of (3R,4S)-pyrrolidine-3,4-diolhydrochloride and 55 μl (310 μmol) of DIPEA in 410 μl of DMF. The crudeproduct was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 20.0 mg (43% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.72 min; MS (ESIpos): m/z=513 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.44 (d, 1H), 8.75 (s, 1H), 8.28 (d,1H), 7.67-7.75 (m, 1H), 7.38-7.45 (m, 2H), 6.76 (d, 1H), 5.03 (d, 1H),4.91 (d, 1H), 4.68-4.78 (m, 1H), 4.08-4.15 (m, 1H), 3.97-4.05 (m, 1H),3.56-3.63 (m, 1H), 3.24-3.30 (m, 1H), 3.14-3.22 (m, 1H), 2.92-3.01 (m,1H), 1.83-1.93 (m, 1H), 1.58-1.70 (m, 1H), 0.97 (t, 3H).

Example 6491-(2,6-Dichloro-4-fluorophenyl)-4-oxo-7-(2-oxoimidazolidin-1-yl)-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 60.0 mg (121 μmol) of the compound from Example 131Awere reacted with 104 mg (1.21 mmol) of imidazolidin-2-one in thepresence of 25.0 mg (181 μmol) of potassium carbonate, 5.42 mg (24.2μmol) of palladium acetate and 14.0 mg (24.2 μmol) of Xantphos in 1.1 mlof 1,4-dioxane. The crude product was purified by means of preparativeHPLC (acetonitrile/water/0.1% formic acid). The substance was isolatedwith impurities and was further recrystallized from acetonitrile,filtered off with suction, washed with a little acetonitrile and dried.24.3 mg (37% of theory, 100% purity) of the title compound wereobtained.

LC-MS (Method 3): R_(t)=2.03 min; MS (ESIpos): m/z=546 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.25 (d, 1H), 8.92 (s, 1H), 8.57 (d,1H), 8.43 (d, 1H), 7.89 (d, 2H), 7.66 (s, 1H), 4.71-4.82 (m, 1H),3.47-3.55 (m, 2H), 3.32-3.37 (m, 2H), 1.84-1.94 (m, 1H), 1.61-1.73 (m,1H), 0.98 (t, 3H).

Example 6507-(4-Carbamoylpiperazin-1-yl)-N-[(1R)-1-cyclopropyl-2,2,2-trifluoroethyl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 80.0 mg (179 μmol) of the compound from Example 168Awere reacted with 37.7 mg (215 μmol) of(1R)-1-cyclopropyl-2,2,2-trifluoroethanamine hydrochloride in thepresence of 81.6 mg (215 μmol) of HATU and 120 μl (720 μmol) of DIPEA in690 μl of DMF. The crude product was purified by means of preparativeHPLC (acetonitrile/water/0.1% formic acid). 74.1 mg (73% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.74 min; MS (ESIpos): m/z=569 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.50 (d, 1H), 8.83 (s, 1H), 8.32 (d,1H), 7.54-7.61 (m, 2H), 7.15 (d, 1H), 6.03 (s, 2H), 4.33-4.43 (m, 1H),3.44-3.52 (m, 4H), 3.31-3.35 (m, 4H), 1.16-1.25 (m, 1H), 0.50-0.69 (m,3H), 0.30-0.38 (m, 1H).

Example 651N-(2,6-Dichlorophenyl)-1-(2,4-difluorophenyl)-7-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP3, 40.0 mg (83.2 μmol) of the compound from Example 81Awere reacted with 13.9 mg (99.9 μmol) of (3R,4S)-pyrrolidine-3,4-diolhydrochloride and 51 μl (290 μmol) of DIPEA in 400 μl of DMF. The crudeproduct was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 32.8 mg (72% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.74 min; MS (ESIpos): m/z=547 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=12.03 (s, 1H), 8.68 (s, 1H), 8.33 (d,1H), 7.80-7.89 (m, 1H), 7.53-7.63 (m, 3H), 7.30-7.40 (m, 2H), 6.76 (d,1H), 4.99-5.07 (m, 1H), 4.91-4.98 (m, 1H), 4.10-4.18 (m, 1H), 3.98-4.09(m, 1H), 3.55-3.66 (m, 1H), 3.17-3.29 (m, 2H), 2.95-3.09 (m, 1H).

Example 6521-(2,6-Dichlorophenyl)-7-[1-hydroxy-3-azabicyclo[3.1.0]hex-3-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP3, 72.7 mg (152 μmol) of the compound from Example 166Cwere reacted with 27.2 mg (182 μmol, 91% purity) of3-azabicyclo[3.1.0]hexan-1-ol and 93 μl (530 μmol) of DIPEA in 640 μl ofDMF. The crude product was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 62.6 mg (76% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.09 min; MS (ESIpos): m/z=541 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.45 (d, 1H), 8.65 (s, 1H), 8.29 (d,1H), 7.72-7.81 (m, 2H), 7.61-7.72 (m, 1H), 6.69-6.81 (m, 1H), 5.87-6.08(m, 1H), 4.68-4.79 (m, 1H), 3.82-3.90 (m, 0.40H), 3.58-3.70 (m, 0.60H),3.35-3.55 (m, 1.60H), 3.13-3.21 (m, 0.40H), 2.96-3.10 (m, 1H), 1.83-1.93(m, 1H), 1.48-1.71 (m, 2H), 0.92-1.04 (m, 4H), 0.36-0.44 (m, 1H).

Example 653N-(Bicyclo[1.1.1]pent-1-yl)-4-oxo-7-(2-oxoimidazolidin-1-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 50.0 mg (124 μmol) of the compound from Example 113Awere reacted with 17.7 mg (148 μmol) of bicyclo[1.1.1]pentan-1-aminehydrochloride in the presence of 56.4 mg (148 μmol) of HATU and 86 μl(490 μmol) of DIPEA in 750 μl of DMF. The crude product was purified bymeans of preparative HPLC (acetonitrile/water/0.1% formic acid). 36.5 mg(63% of theory, 100% purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.84 min; MS (ESIpos): m/z=470 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.08 (s, 1H), 8.85 (s, 1H), 8.52 (d,1H), 8.41 (d, 1H), 7.65 (s, 1H), 7.57 (t, 2H), 3.55-3.62 (m, 2H),3.32-3.37 (m, 2H), 2.11 (s, 6H).

Example 6541-(2,6-Dichloro-4-fluorophenyl)-4-oxo-7-(2-oxoimidazolidin-1-yl)-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP2, 60.0 mg (121 μmol) of the compound from Example 132Awere reacted with 104 mg (1.21 mmol) of imidazolidin-2-one in thepresence of 25.0 mg (181 μmol) of potassium carbonate, 5.42 mg (24.2μmol) of palladium acetate and 14.0 mg (24.2 μmol) of Xantphos in 1.1 mlof 1,4-dioxane. The crude product was purified by means of preparativeHPLC (acetonitrile/water/0.1% formic acid). The substance was isolatedwith impurities and was further recrystallized from acetonitrile,filtered off with suction, washed with a little acetonitrile and dried.46.6 mg (71% of theory, 100% purity) of the title compound wereobtained.

LC-MS (Method 3): R_(t)=2.03 min; MS (ESIpos): m/z=546 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.25 (d, 1H), 8.92 (s, 1H), 8.57 (d,1H), 8.43 (d, 1H), 7.89 (d, 2H), 7.66 (s, 1H), 4.70-4.81 (m, 1H),3.47-3.55 (m, 2H), 3.32-3.37 (m, 2H), 1.84-1.95 (m, 1H), 1.61-1.73 (m,1H), 0.98 (t, 3H).

Example 655N-(3,3-Difluoro-1-methylcyclobutyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 50.0 mg (119 μmol) of the compound 121A were reactedwith 22.4 mg (142 μmol) of 3,3-difluoro-1-methylcyclobutanaminehydrochloride in the presence of 54.1 mg (142 μmol) of HATU and 83 μl(470 μmol) of DIPEA in 750 μl of DMF. The crude product was purified bymeans of preparative HPLC (acetonitrile/water/0.1% formic acid). 39.6 mg(64% of theory, 100% purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.59 min; MS (ESIpos): m/z=525 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.28 (s, 1H), 8.70 (s, 1H), 8.26 (d,1H), 7.53-7.60 (m, 2H), 6.76 (d, 1H), 5.23 (d, 1H), 5.14 (d, 1H), 4.04(br s, 1H), 3.92 (br s, 1H), 3.61 (br dd, 1H), 3.32-3.36 (m, 1H), 3.24(br dd, 1H), 2.97-3.10 (m, 3H), 2.70 (td, 2H), 1.55 (s, 3H).

Example 656N-(3,3-Difluoro-1-methylcyclobutyl)-4-oxo-7-(2-oxoimidazolidin-1-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 50.0 mg (124 μmol) of the compound from Example 113Awere reacted with 23.4 mg (148 μmol) of3,3-difluoro-1-methylcyclobutanamine hydrochloride in the presence of56.4 mg (148 μmol) of HATU and 86 μl (490 μmol) of DIPEA in 750 μl ofDMF. The crude product was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 37.9 mg (60% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.83 min; MS (ESIpos): m/z=508 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.08 (s, 1H), 8.89 (s, 1H), 8.54 (d,1H), 8.42 (d, 1H), 7.65 (s, 1H), 7.57 (t, 2H), 3.55-3.62 (m, 2H),3.32-3.38 (m, 2H), 2.98-3.10 (m, 2H), 2.68-2.77 (m, 2H), 1.57 (s, 3H).

Example 6571-(2,4-Difluorophenyl)-7-[4-hydroxy-3,3,5-trimethyl-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP2, 31.1 mg (69.8 μmol) of the compound from Example 67Awere reacted with 12.0 mg (83.8 μmol) of the compound from Example 164Cin the presence of 14.5 mg (105 μmol) of potassium carbonate, 3.14 mg(14.0 μmol) of palladium acetate and 8.08 mg (14.0 μmol) of Xantphos in620 μl of 1,4-dioxane. The crude product was purified by means ofpreparative HPLC (acetonitrile/water/0.1% formic acid). 20.0 mg (52% oftheory, 100% purity) of the title compound were obtained.

LC-MS (Method 4): R_(t)=3.72 min; MS (ESIpos): m/z=553 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.21 (br d, 1H), 8.84-8.89 (m, 1H),8.70 (dd, 1H), 8.49 (dd, 1H), 7.84-7.93 (m, 1H), 7.49-7.75 (m, 1H),7.29-7.41 (m, 1H), 5.40 (d, 1H), 4.71-4.83 (m, 1H), 4.03-4.13 (m, 1H),3.93-4.03 (m, 1H), 1.82-1.95 (m, 1H), 1.60-1.73 (m, 1H), 0.85-1.11 (m,12H).

Example 6587-[(4S)-4-Hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluoro-4-methylpentan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP1, 50.0 mg (119 μmol) of the compound from Example 117Awere reacted with 27.4 mg (143 μmol) of(2S)-1,1,1-trifluoro-4-methylpentan-2-amine hydrochloride in thepresence of 54.4 mg (143 μmol) of HATU and 62 μl (360 μmol) of DIPEA in460 μl of DMF. The crude product was purified by means of preparativeHPLC (acetonitrile/water/0.1% formic acid). 42.5 mg (62% of theory, 97%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=2.10 min; MS (ESIpos): m/z=557 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.10 (d, 1H), 9.08 (s, 1H), 8.71 (d,1H), 8.54 (d, 1H), 7.58-7.65 (m, 2H), 5.34 (d, 1H), 4.81-4.89 (m, 1H),4.27-4.31 (m, 1H), 3.69 (dd, 1H), 3.48 (d, 1H), 2.94 (dd, 1H), 2.38 (brd, 1H), 1.65-1.74 (m, 2H), 1.54-1.62 (m, 1H), 0.95 (d, 3H), 0.90 (d,3H).

Example 659N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP2, 150.0 mg (315 μmol) of the compound from Example 126Awere reacted with 44.3 mg (378 μmol) of5-(hydroxymethyl)-1,3-oxazolidin-2-one (racemate) in the presence of65.4 mg (473 μmol) of potassium carbonate, 14.2 mg (63.1 μmol) ofpalladium acetate and 36.5 mg (63.1 μmol) of Xantphos in 1.5 ml of1,4-dioxane. The crude product was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). 17.4 mg (10% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.92 min; MS (ESIpos): m/z=557 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.53 (d, 1H), 8.81 (s, 1H), 8.32-8.44(m, 1H), 8.24 (d, 1H), 7.50-7.59 (m, 2H), 6.78 (br d, 1H), 4.67-4.78 (m,1H), 4.33-4.44 (m, 2H), 4.02 (br t, 1H), 3.32-3.46 (m, 2H), 1.16-1.25(m, 1H), 0.49-0.69 (m, 3H), 0.30-0.37 (m, 1H).

Example 660N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP3, 100 mg (210 μmol) of the compound from Example 126Awere reacted with 25.5 mg (250 μmol) of (2S)-pyrrolidin-2-ylmethanol and110 μl (630 μmol) of DIPEA in 850 μl of DMF. The crude product waspurified by means of preparative HPLC (acetonitrile/water/0.1% formicacid). 93.6 mg (82% of theory, 100% purity) of the title compound wereobtained.

LC-MS (Method 3): R_(t)=2.05 min; MS (ESIpos): m/z=541 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.57 (d, 1H), 8.80 (s, 1H), 8.28 (brd, 1H), 7.46-7.57 (m, 2H), 6.72-6.97 (m, 1H), 4.85-4.94 (m, 0.40H),4.42-4.50 (m, 0.60H), 4.31-4.42 (m, 1H), 3.94-4.04 (br d, 0.40H),3.66-3.76 (m, 0.60H), 3.34-3.54 (m, 2H), 3.05-3.28 (m, 2H), 1.75-2.07(m, 4H), 1.16-1.25 (m, 1H), 0.49-0.69 (m, 3H), 0.30-0.37 (m, 1H).

Example 661 N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP3, 100 mg (210 μmol) of the compound from Example 126Awere reacted with 29.8 mg (294 μmol) of (2R)-pyrrolidin-2-ylmethanol and110 μl (630 μmol) of DIPEA in 850 μl of DMF. The crude product waspurified by means of preparative HPLC (acetonitrile/water/0.1% formicacid). 109 mg (96% of theory, 100% purity) of the title compound wereobtained.

LC-MS (Method 3): R_(t)=2.06 min; MS (ESIpos): m/z=541 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.57 (br d, 1H), 8.80 (s, 1H), 8.28(br d, 1H), 7.46-7.58 (m, 2H), 6.85-6.98 (m, 0.40H), 6.72-6.85 (m,0.60H), 4.83-4.96 (m, 0.40H), 4.43-4.50 (m, 0.60H), 4.32-4.43 (m, 1H),3.94-4.04 (m, 0.40H), 3.66-3.78 (m, 0.60H), 3.34-3.55 (m, 2H), 3.03-3.27(m, 2H), 1.76-2.06 (m, 4H), 1.15-1.26 (m, 1H), 0.50-0.69 (m, 3H),0.31-0.38 (m, 1H).

Example 662N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-(3-hydroxyazetidin-1-yl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP3, 200 mg (420 μmol) of the compound from Example 126Awere reacted with 64.5 mg (589 μmol) of azetidin-3-ol hydrochloride and220 μl (1.30 mmol) of DIPEA in 1.7 ml of DMF. The crude product waspurified by means of preparative HPLC (acetonitrile/water/0.1% formicacid). 180 mg (83% of theory, 100% purity) of the title compound wereobtained.

LC-MS (Method 3): R_(t)=1.91 min; MS (ESIpos): m/z=513 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.53 (d, 1H), 8.79 (s, 1H), 8.28 (d,1H), 7.50-7.58 (m, 2H), 6.61 (d, 1H), 5.73 (d, 1H), 4.49-4.57 (m, 1H),4.34-4.42 (m, 1H), 3.89-4.30 (m, 2H), 3.47-3.85 (m, 2H), 1.16-1.25 (m,1H), 0.49-0.69 (m, 3H), 0.30-0.37 (m, 1H).

Example 663 N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[4-hydroxy-4-(hydroxymethyl)piperidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP3, 100 mg (210 μmol) of the compound from Example 126Awere reacted with 38.6 mg (294 μmol) of 4-(hydroxymethyl)piperidin-4-oland 110 μl (630 μmol) of DIPEA in 850 μl of DMF. The crude product waspurified by means of preparative HPLC (acetonitrile/water/0.1% formicacid). 78.7 mg (66% of theory, 100% purity) of the title compound wereobtained.

LC-MS (Method 3): R_(t)=1.80 min; MS (ESIpos): m/z=571 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.54 (d, 1H), 8.80 (s, 1H), 8.26 (d,1H), 8.16 (s, 1H), 7.56 (t, 2H), 7.14 (d, 1H), 4.47-4.68 (m, 1H),4.23-4.47 (m, 2H), 3.93 (br d, 2H), 3.15 (s, 2H), 1.27-1.52 (m, 4H),1.16-1.25 (m, 1H), 0.49-0.69 (m, 3H), 0.34 (dq, 1H).

Example 6647-[Bis(2-hydroxyethyl)amino]-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to GP3, 100 mg (210 μmol) of the compound from Example 126Awere reacted with 30.9 mg (294 μmol) of 2,2′-iminodiethanol and 110 μl(630 μmol) of DIPEA in 850 μl of DMF. The crude product was purified bymeans of preparative HPLC (acetonitrile/water/0.1% formic acid). 87.5 mg(76% of theory, 100% purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.71 min; MS (ESIpos): m/z=545 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.56 (d, 1H), 8.81 (s, 1H), 8.25 (d,1H), 7.50-7.57 (m, 2H), 7.01 (d, 1H), 4.72-4.90 (m, 1H), 4.54-4.72 (m,1H), 4.33-4.43 (m, 1H), 3.52-3.68 (m, 4H), 3.18-3.29 (m, 2H), 1.16-1.25(m, 1H), 0.50-0.69 (m, 3H), 0.30-0.38 (m, 1H).

Example 665 N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[3-hydroxy-3-methylpiperidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide(Diastereomer Mixture)

According to GP3, 200 mg (420 μmol) of the compound from Example 126Awere reacted with 67.8 mg (589 μmol) of 3-methylpiperidin-3-ol and 220μl (1.3 mmol) of DIPEA in 1.7 ml of DMF. The crude product was purifiedby means of preparative HPLC (acetonitrile/water/0.1% formic acid). 220mg (94% of theory, 100% purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=2.11 min; MS (ESIpos): m/z=555 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.56 (s, 1H), 8.78 (s, 1H), 8.22 (d,1H), 7.53-7.60 (m, 2H), 7.09 (d, 1H), 4.33-4.44 (m, 2H), 3.34-3.80 (m,2H), 1.45-1.68 (m, 3H), 1.28-1.42 (m, 1H), 1.15-1.25 (m, 1H), 0.90-1.09(m, 3H), 0.49-0.69 (m, 3H), 0.29-0.37 (m, 1H).

Example 666 Methyl(5S)-3-[6-{[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]carbamoyl}-5-oxo-8-(2,4,6-trifluorophenyl)-5,8-dihydro-1,8-naphthyridin-2-yl]-2-oxo-1,3-oxazolidine-5-carboxylate

According to GP2, 1.00 g (2.10 mmol) of the compound from Example 126Awere reacted with 366 mg (2.52 mmol) of methyl(5S)-2-oxo-1,3-oxazolidine-5-carboxylate in the presence of 436 mg (3.15mmol) of potassium carbonate, 94.4 mg (420 μmol) of palladium acetateand 243 mg (420 μmol) of Xantphos in 10 ml of 1,4-dioxane. The crudeproduct was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). The substance was isolated withimpurities and was further recrystallized from acetonitrile, filteredoff with suction and dried. 515 mg (42% of theory, 100% purity) of thetitle compound were obtained.

LC-MS (Method 3): R_(t)=2.11 min; MS (ESIpos): m/z=585 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.23 (d, 1H), 9.07 (s, 1H), 8.76 (d,1H), 8.29 (d, 1H), 7.57-7.65 (m, 2H), 5.27 (dd, 1H), 4.35-4.45 (m, 1H),4.04 (t, 1H), 3.85 (dd, 1H), 3.73 (s, 3H), 1.19-1.28 (m, 1H), 0.53-0.70(m, 3H), 0.31-0.39 (m, 1H).

Example 667(5S)-3-[6-{[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]carbamoyl}-5-oxo-8-(2,4,6-trifluorophenyl)-5,8-dihydro-1,8-naphthyridin-2-yl]-2-oxo-1,3-oxazolidine-5-carboxylicacid

To a solution of 470 mg (804 μmol) of the compound from Example 666 in21.4 ml of a mixture of THF and water (3:1, v/v) were added, at 0° C.,33.7 mg (804 μmol) of lithium hydroxide monohydrate dissolved in water.The mixture was stirred at 0° C. for 1 h. Subsequently, the reactionsolution was added to water containing a little 1N aqueous hydrochloricacid and extracted three times with ethyl acetate. The combined organicphases were washed with saturated aqueous sodium chloride solution anddried over sodium sulphate. The solvent was removed under reducedpressure, and the substance was recrystallized from a littleacetonitrile and dried under high vacuum. 363 mg (79% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.75 min; MS (ESIpos): m/z=571 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=13.73 (br s, 1H), 10.23 (d, 1H), 9.07(s, 1H), 8.75 (d, 1H), 8.29 (d, 1H), 7.57-7.65 (m, 2H), 5.16 (dd, 1H),4.35-4.45 (m, 1H), 4.04 (t, 1H), 3.77 (dd, 1H), 1.19-1.28 (m, 1H),0.52-0.70 (m, 3H), 0.31-0.38 (m, 1H).

Example 668 7-[(5S)-5-Carbamoyl-2-oxo-1,3-oxazolidin-3-yl]-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

To a solution of 327 mg (556 μmol) of the compound from Example 169A in12 ml of THF were added dropwise 11 ml (0.50 M in dioxane, 5.60 mmol) ofammonia, and the reaction mixture was stirred at room temperature for 1h. The solvent was removed under reduced pressure and the residue waspurified by means of preparative HPLC (acetonitrile/water/0.1% formicacid). 311 mg (98% of theory, 100% purity) of the title compound wereobtained.

LC-MS (Method 3): R_(t)=1.80 min; MS (ESIpos): m/z=570 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.23 (d, 1H), 9.06 (s, 1H), 8.75 (d,1H), 8.31 (d, 1H), 7.83 (s, 1H), 7.54-7.65 (m, 3H), 4.99 (dd, 1H),4.35-4.46 (m, 1H), 3.99 (t, 1H), 3.67 (dd, 1H), 1.19-1.28 (m, 1H),0.53-0.70 (m, 3H), 0.31-0.39 (m, 1H).

Example 669 Methyl(5R)-3-[6-{[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]carbamoyl}-5-oxo-8-(2,4,6-trifluorophenyl)-5,8-dihydro-1,8-naphthyridin-2-yl]-2-oxo-1,3-oxazolidine-5-carboxylate

According to GP2, 1.00 g (2.10 mmol) of the compound from Example 126Awere reacted with 366 mg (2.52 mmol) of methyl(5R)-2-oxo-1,3-oxazolidine-5-carboxylate in the presence of 436 mg (3.15mmol) of potassium carbonate, 94.4 mg (420 μmol) of palladium acetateand 243 mg (420 μmol) of Xantphos in 10 ml of 1,4-dioxane. The crudeproduct was purified by means of preparative HPLC(acetonitrile/water/0.1% formic acid). The substance was isolated withimpurities and was further recrystallized from acetonitrile, filteredoff with suction and dried. 631 mg (51% of theory, 99% purity) of thetitle compound were obtained.

LC-MS (Method 3): R_(t)=2.11 min; MS (ESIpos): m/z=585 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=10.22 (d, 1H), 9.07 (s, 1H), 8.76 (d,1H), 8.28 (d, 1H), 7.58-7.65 (m, 2H), 5.27 (dd, 1H), 4.35-4.45 (m, 1H),4.04 (t, 1H), 3.85 (dd, 1H), 3.73 (s, 3H), 1.19-1.28 (m, 1H), 0.53-0.70(m, 3H), 0.31-0.38 (m, 1H).

Example 670(5R)-3-[6-{[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]carbamoyl}-5-oxo-8-(2,4,6-trifluorophenyl)-5,8-dihydro-1,8-naphthyridin-2-yl]-2-oxo-1,3-oxazolidine-5-carboxylicacid

To a solution of 589 mg (1.01 mmol) of the compound from Example 669 in26.8 ml of a mixture of THF and water (3:1, v/v) were added, at 0° C.,42.3 mg (1.01 mmol) of lithium hydroxide monohydrate dissolved in water.The mixture was stirred at 0° C. for 1 h. Subsequently, the reactionsolution was added to water containing a little 1N aqueous hydrochloricacid and extracted three times with ethyl acetate. The combined organicphases were washed with a little saturated aqueous sodium chloridesolution and dried over sodium sulphate. The solvent was removed underreduced pressure, and the substance was recrystallized from a littleacetonitrile and dried under high vacuum. 485 mg (84% of theory, 100%purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.75 min; MS (ESIpos): m/z=571 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ ppm=13.73 (br s, 1H), 10.23 (d, 1H), 9.07(s, 1H), 8.75 (d, 1H), 8.29 (d, 1H), 7.58-7.65 (m, 2H), 5.16 (dd, 1H),4.35-4.45 (m, 1H), 4.04 (t, 1H), 3.77 (dd, 1H), 1.19-1.28 (m, 1H),0.53-0.70 (m, 3H), 0.31-0.38 (m, 1H).

Example 6717-[(5R)-5-Carbamoyl-2-oxo-1,3-oxazolidin-3-yl]-N-[(15)-1-cyclopropyl-2,2,2-trifluoroethyl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

To a solution of 454 mg (771 μmol) of the compound from Example 170A in18 ml of THF were added 15 ml (0.50 M in dioxane, 7.70 mmol) of ammonia,and the reaction mixture was stirred at room temperature for 1 h. Thesolvent was removed under reduced pressure and the residue was purifiedby means of preparative HPLC (acetonitrile/water/0.1% formic acid). 421mg (96% of theory, 100% purity) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.79 min; MS (ESIpos): m/z=570 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.23 (d, 1H), 9.06 (s, 1H), 8.75 (d,1H), 8.31 (d, 1H), 7.83 (s, 1H), 7.54-7.65 (m, 3H), 4.99 (dd, 1H),4.35-4.45 (m, 1H), 3.99 (t, 1H), 3.67 (dd, 1H), 1.19-1.28 (m, 1H),0.53-0.70 (m, 3H), 0.31-0.38 (m, 1H).

B. ASSESSMENT OF PHARMACOLOGICAL EFFICACY

The pharmacological activity of the compounds according to the inventioncan be demonstrated by in vitro and in vivo studies, as known to theperson skilled in the art. The application examples which followdescribe the biological action of the compounds according to theinvention, without restricting the invention to these examples.

Abbreviations and Acronyms

B_(Max) number of specific binding sites of the radioligandCAFTY calcium free tyrodeCHO chinese hamster ovaryCRE cAMP-responsive elementDMEM Dulbecco's modified eagle mediumDMSO dimethyl sulphoxideFCS foetal calf serumFRET fluorescence resonance energy transferGIRK1/4 G-protein-coupled inward rectifier potassium channel, member 1/4HEPES hydroxyethylpiperazine-ethanesulphonic acidHTRF homogeneous time resolved fluorescenceK_(d) equilibrium dissociation constantK_(i) equilibrium inhibitor constantk_(off) rate of dissociationk_(on) rate of associationnM nanomolarMEM minimum essential mediumμl microlitresμM micromolarml millilitresmM millimolarmtClytin mitochondrial clytinmin minutes

NMS N-Me-scopolamine

PAM positive allosteric modulatorPEI polyethyleneiminePen/Strep penicillin/streptomycinsec seconds

B-1. Functional M2-GIRK1/4 Activation Test

Both the activation of the M2 receptor by orthosteric agonists alone andthe allosteric boosting of orthosterically induced activation bypositive allosteric modulators (PAMs) can be determined by means of acell-based functional GIRK1/4 activity test. The binding of orthostericagonists (endogenous ligand: acetylcholine) to the M2 receptor leads toreceptor activation or a change in conformation of the receptor in themanner of a shift in equilibrium in favour of the active receptorconformation. The binding of the orthosteric agonists to the M2 receptorand hence the activation thereof can be boosted by positive allostericmodulators which bind not to the orthosteric binding site of theagonists but to a separate allosteric binding site.

The agonist-induced change in conformation of the M2 receptor results ina Gαi protein activation. The activation of the Gα subunit leads in turnto dissociation and hence release of the Gβγ subunits from the Gαsubunit and the activation of separate downstream signal transductioncascades. The heterodimeric Gβγ complex released binds to the GIRK1/4potassium channel and induces a ligand-controlled channel activation oropening (Reuveny et al., Nature, July 1994, 370, 143-146). Underphysiological conditions, the result is then a selective efflux ofpotassium from the cell along the electrochemical gradient. The exportof positive charge leads to lowering of the transmembrane potential andhence to hyperpolarization of the cell. The extent of hyperpolarizationcan therefore be regarded as a measure of the activation of the M2receptor.

The test cell used is a recombinant CHO-DUKX cell line which has beenstably transfected with cDNA coding for the human M2 receptor and withcDNA coding for both GIRK1/4 subunits (CHO-DUKX-M2-GIRK). Thetransmembrane potential, or the relative changes in the transmembranepotential as a function of substance addition or M2 activation, isdetermined by means of a voltage-sensitive dye (FLIPR Membrane PotentialAssay Kit Blue, Molecular Devices # R8034) and the measurement of cellfluorescence using a proprietary fluorescence imaging instrument.

B-1.1. Determination of the Allosteric Potency of the Test Substances(EC₅₀ Value)

The test substances are dissolved in dimethyl sulphoxide (DMSO) at aconcentration of 10 mM and serially diluted with DMSO in steps of 1:3.16for a 10-point dose/activity analysis. In accordance with the desiredtest concentrations, the substances are pre-diluted in loading buffer(composition: 0.6 ml of FLIPR Membrane Potential Assay Kit Blue (10mg/ml), 0.6 ml of Brilliant Black (10 mg/ml), 2 mM CaCl₂ and 2 mM KCl ad50 ml sodium gluconate Tyrode (PAA, #T21-155)).

The reporter cells cultivated in MEM alpha medium (supplemented with 10%FCS, 2% Glutamax, 1 mg/ml genticin) were sown with 2000 cells(measurement after 48 h) or 4000 cells (measurement after 24 h) in 30 μlper 384-well in pCLEAR/schwarz Greiner cell culture plates (#781092) andincubated at 37° C. for 24 h or 48 h. The sowing medium consisted of MEMalpha medium (supplemented with 5% FCS, 2% Glutamax, no genticin).

For the particular measurement, the medium was removed and the cellswere laden with the voltage-sensitive dye for at least 6 min at roomtemperature (30 μl of loading buffer per 384-well). This was followed,in a first measurement, by the determination of the fluorescence for theresting transmembrane potential for a period of 5 sec. Thereafter, 10 μlin each case of the test substances diluted in loading buffer wereadded, followed by a second measurement to determine the transmembranepotential for a period of 50 sec. Finally, the cells were admixed with10 μl of agonist solution (acetylcholine dissolved in loading buffer).Acetylcholine was used at the concentration corresponding to the EC₂₀,which had been determined in a preliminary test. The M2-mediated GIRK1/4activation or hyperpolarization was then monitored in a thirdmeasurement over a period of 60 sec. The EC₅₀ value (degree ofallosteric potency of test compound) and the efficiency (measure of theboosting of the acetylcholine effect at an EC₂₀ acetylcholineconcentration) were determined with the aid of a 4-parameter logisticfunction (Hill function).

B-1.2. Determination of Positive Cooperativity (α Factor)

The test substances were dissolved in DMSO at a concentration of 10 mMand serially diluted with DMSO in steps of 1:3.16 for a 10-pointdose/activity analysis. In accordance with the desired testconcentrations, the substances were pre-diluted in loading buffer (seeabove).

The reporter cells cultivated in MEM alpha medium (supplemented with 10%FCS, 2% Glutamax, 1 mg/ml genticin) are sown with 2000 cells(measurement after 48 h) or 4000 cells (measurement after 24 h) in 30 μlper 384-well in μCLEAR/schwarz Greiner cell culture plates (#781092) andincubated at 37° C. for 24 h or 48 h. The sowing medium consisted of MEMalpha medium (supplemented with 5% FCS, 2% Glutamax, no genticin).

For the particular measurement, the medium was removed and the cellswere laden with the voltage-sensitive dye for at least 6 min at roomtemperature (30 μl of loading buffer per 384-well). This was followed,in a first measurement, by the determination of the restingtransmembrane potential for a period of 5 sec in 1 sec increments.Thereafter, 10 μl in each case of the test substances diluted in loadingbuffer are added, followed by a second measurement to determine thetransmembrane potential for a period of 50 sec in 1 sec increments.

Finally, the cells are admixed with 10 μl of agonist solution(acetylcholine dissolved in loading buffer). In contrast to the EC₅₀determination of the test substances (see B-1.1), however, this is notdone using one acetylcholine concentration; instead, every concentrationof the test substance is combined with an acetylcholine 8-pointdose-response curve. For the acetylcholine dilution series, the agonistis serially pre-diluted in loading buffer in accordance with the desiredend concentrations, starting with a maximum end concentration of 3 μM insteps of 1:3.16. The M2-mediated GIRK1/4 activation or hyperpolarizationis then monitored in a third measurement over a period of 60 sec in 1sec increments. The shift in the acetylcholine dose-response curve inthe presence of increasing concentrations of the test substance isanalysed and quantified by means of GraphPad PRISM (Allosteric EC₅₀shift). The α factor determined is a measure of the strength anddirection of the allosteric effect. α values >1 reflect a lowering ofthe EC₅₀ value or an increase in the potency of the agonist(acetylcholine) in the presence of allosterics and mean positivecooperativity between orthosterics (acetylcholine) and allosterics (testsubstance). Positive cooperativity is the hallmark of a positiveallosteric modulator. Conversely, α values <1 are indicative of negativecooperativity between orthosterics and allosterics, and hencecharacterize negative allosteric modulators. α values=1 mean nocooperativity between orthosteric and allosteric, meaning that thebinding affinities of orthosteric and allosteric to the receptor do notaffect one another. The greater the magnitude of the α value, thegreater the extent of cooperativity between orthosteric and allosteric.

Table 1 below lists, for individual working examples, the EC₅₀ andefficiency values thus determined and the α values from this assay (insome cases as mean values from two or more independent individualdeterminations):

TABLE 1 Receptor activity Cooperativity Ex. EC₅₀ Efficiency (alpha No.[μmol/l] [%] factor) 1 0.014 97.5 11 2 0.017 100.0 24 3 0.017 99.8 30 40.024 99.8 30 5 0.031 98.7 6 0.034 98.8 15 7 0.034 100.0 34 8 0.038 98.09 0.040 96.5 11 10 0.060 98.5 12 11 0.061 99.3 10 12 0.064 95.0 13 0.07195.8 6 14 0.082 97.7 15 0.085 90.5 8 16 0.090 97.3 17 0.159 97.3 180.117 97.3 19 0.058 95.0 12 20 0.042 98.4 34 21 0.145 100.0 22 0.13197.7 23 0.096 99.3 20 24 0.063 100.0 25 25 0.084 100.0 20 26 0.164 97.027 0.089 97.7 20 28 0.023 100.0 25 29 0.112 95.3 4 30 0.095 93.3 11 310.040 97.0 13 32 0.173 93.5 33 0.091 96.7 20 34 0.095 99.7 35 0.062 98.824 36 0.019 96.1 16 37 0.023 96.3 38 0.041 100.0 14 39 0.088 92.1 14 400.106 94.2 41 0.039 99.4 42 0.017 94.5 43 0.141 96.6 44 0.111 98.3 12 450.028 99.7 46 0.127 98.7 47 0.043 100.0 48 0.110 94.8 49 0.089 86.0 500.158 95.0 51 0.100 95.0 52 0.104 98.5 53 0.058 100.0 54 0.085 98.3 550.036 99.8 25 56 0.056 100.0 15 57 0.082 93.8 7 58 0.077 100.0 9 590.094 97.0 11 60 0.155 100.0 8 61 0.016 98.2 62 0.017 95.5 63 0.040 88.064 0.012 89.7 28 65 0.007 93.7 36 66 0.010 92.0 67 0.138 78.0 68 0.05897.5 69 0.013 99.5 70 0.076 97.4 29 71 0.039 95.0 30 72 0.053 94.0 730.073 91.9 74 0.058 87.0 75 0.073 87.0 76 0.069 96.0 77 0.666 100.0 780.079 94.3 79 0.144 92.2 80 0.073 94.0 81 0.102 89.7 82 0.060 100.0 830.110 88.9 84 0.077 100.0 85 0.118 98.5 26 86 0.108 94.5 87 0.129 94.026 88 0.042 95.0 89 0.413 96.6 20 90 0.298 94.7 11 91 0.058 90.5 920.174 95.5 93 0.213 85.7 8 94 0.164 98.7 95 0.144 90.0 96 0.134 92.3 970.209 95.0 9 98 0.061 97.4 14 99 0.182 92.7 100 0.143 96.3 101 0.02676.8 102 0.031 94.0 103 0.050 95.7 104 0.028 96.0 15 105 0.146 97.7 1060.032 100.0 107 0.057 91.8 14 108 0.024 95.0 109 0.187 95.0 110 0.06298.0 111 0.035 100.0 26 112 0.029 85.5 113 0.141 91.0 114 0.098 93.3 1150.073 91.0 116 0.059 93.7 117 0.089 90.5 118 0.091 91.0 119 0.090 94.3120 0.062 86.5 121 0.295 88.3 8 122 0.094 87.7 123 0.115 97.7 14 1240.155 88.5 125 0.116 93.0 126 0.180 81.0 127 0.077 86.5 128 0.057 91.718 129 0.045 88.1 130 0.113 90.0 131 0.157 89.8 132 0.010 98.0 7 1330.019 94.0 134 0.032 92.5 135 0.017 91.0 8 136 0.024 81.5 137 0.016 97.0138 0.068 100.0 139 0.065 100.0 140 0.068 99.0 141 0.083 99.4 142 0.110100.0 143 0.037 95.5 144 0.032 92.7 145 0.030 100.0 146 0.026 95.8 1470.082 94.9 148 0.041 94.9 149 0.085 100.0 150 0.072 90.5 151 0.023 86.4152 0.010 97.0 153 0.104 100.0 154 0.158 97.6 155 0.173 97.7 156 0.08684.7 157 0.067 100.0 158 0.184 100.0 159 0.117 88.9 160 0.085 92.5 1610.137 99.5 162 0.038 93.2 163 0.173 92.8 13 164 0.031 97.3 21 165 0.01140.5 166 0.014 99.0 167 0.047 95.0 168 0.060 95.0 13 169 0.101 79.5 1700.019 96.5 171 0.030 90.5 172 0.083 87.3 173 0.088 100.0 174 0.113 98.625 175 0.069 97.3 33 176 0.095 94.1 28 177 0.138 82.4 5 178 0.197 81.3179 0.169 63.3 180 0.115 96.6 181 0.059 94.5 36 182 0.182 94.8 183 0.16698.0 184 0.129 99.0 185 0.156 97.6 186 0.030 94.0 187 0.098 93.5 10 1880.113 98.5 9 189 0.023 90.5 24 190 0.046 93.7 12 191 0.060 85.3 7 1920.054 91.7 9 193 0.036 100.0 50 194 0.140 96.0 16 195 0.343 96.3 1960.137 98.0 197 0.120 92.0 10 198 0.113 96.0 13 199 0.263 96.0 15 2000.293 83.3 201 0.039 94.8 39 202 0.089 93.3 18 203 0.062 92.5 8 2040.034 92.5 8 205 0.105 85.0 4 206 0.107 95.8 14 207 0.035 100.0 18 2080.115 97.5 23 209 0.163 94.7 210 0.285 93.5 211 0.021 94.8 35 212 0.04199.4 54 213 0.019 99.6 55 214 0.107 97.0 43 215 0.178 100.0 216 0.089100.0 35 217 0.036 96.3 18 218 0.153 93.5 33 219 0.106 97.0 33 220 0.11693.0 29 221 0.106 97.5 24 222 0.200 100.0 223 0.084 99.0 30 224 0.15797.5 31 225 0.363 99.7 33 226 0.083 100.0 35 227 0.073 89.5 14 228 0.05198.7 12 229 0.052 100.0 13 230 0.203 66.3 231 0.120 95.4 12 232 0.09791.8 8 233 0.057 100.0 41 234 0.075 89.8 28 235 0.207 98.3 236 0.860100.0 237 0.751 100.0 238 1.640 92.3 239 0.112 99.3 30 240 0.110 90.7 10241 0.021 95.8 18 242 0.090 96.7 10 243 0.015 98.0 33 244 0.022 93.7 58245 0.112 98.0 42 246 0.023 100.0 53 247 0.160 93.0 248 0.330 91.7 2490.505 89.0 250 0.101 95.5 27 251 0.163 100.0 252 0.109 95.5 253 0.483100.0 254 0.337 94.0 255 0.083 96.7 31 256 0.147 95.0 257 0.138 100.0258 0.147 99.3 30 259 0.560 94.5 14 260 0.280 96.5 261 0.075 95.7 13 2620.072 89.0 27 263 0.440 68.5 264 0.530 76.3 265 23.700 100.0 266 0.743100.0 267 0.024 100.0 28 269 0.210 98.0 270 1.600 94.0 271 0.040 91.0 43272 0.033 98.0 55 273 0.044 100.0 274 0.049 99.8 275 0.018 92.8 38 2760.080 100.0 28 277 0.078 98.5 278 0.077 97.5 279 0.066 92.5 34 280 0.04496.5 24 281 0.034 100.0 44 282 0.021 99.5 32 283 0.040 97.0 284 0.06197.8 41 285 0.598 79.9 23 286 0.094 40.0 3 287 0.145 94.8 24 288 0.04084.0 12 289 0.061 94.3 290 0.312 100.0 291 0.673 99.5 292 0.059 90.5 2930.073 88.5 294 0.065 92.5 31 295 0.021 100.0 71 296 0.028 97.4 49 2970.037 97.3 47 298 0.074 94.0 299 0.056 92.0 300 0.054 95.0 301 0.03095.5 12 302 0.017 96.0 303 0.060 95.0 304 0.009 93.0 24 305 0.012 98.523 306 0.052 98.5 21 307 0.014 99.5 36 308 0.030 100.0 309 0.040 96.0310 0.014 94.5 21 311 0.025 95.0 20 312 0.072 97.0 313 0.071 80.0 3140.027 100.0 24 315 0.038 96.3 25 316 0.028 97.0 317 0.026 88.0 318 0.01486.0 319 0.025 95.5 320 0.130 90.0 6 321 0.043 58.5 322 0.040 96.0 3230.014 94.6 16 324 0.034 97.3 325 0.007 93.0 56 326 0.047 100.0 327 0.06995.5 328 0.079 100.0 329 0.076 95.0 16 330 0.041 93.3 29 331 0.033 96.07 332 0.020 99.2 37 333 0.031 94.5 28 334 0.007 84.0 335 0.023 94.5 7336 0.012 92.0 13 337 0.036 68.0 338 0.007 99.0 24 339 0.044 94.0 26 3400.010 100.0 22 341 0.056 86.0 342 0.011 93.7 13 343 0.025 90.5 344 0.05495.5 345 0.059 100.0 346 0.050 96.0 347 0.034 92.5 348 0.061 100.0 3490.004 100.0 52 350 0.006 98.5 42 351 0.017 100.0 352 0.017 100.0 3530.050 99.0 354 0.038 93.0 355 0.085 99.5 356 0.094 92.5 357 0.004 100.063 358 0.024 95.0 31 359 0.013 98.5 360 0.006 100.0 36 361 0.017 100.0362 0.077 97.0 27 363 0.045 95.0 28 364 0.016 93.0 25 365 0.021 97.0 20366 0.035 100.0 36 367 0.100 93.0 368 0.091 100.0 369 0.008 95.0 39 3700.014 97.2 32 371 0.018 97.5 36 372 0.020 100.0 34 373 0.089 100.0 3740.049 60.0 375 0.040 96.0 376 0.016 93.0 377 0.048 99.0 34 378 0.08176.8 379 0.035 95.5 380 0.046 88.0 381 0.023 87.0 382 0.072 91.0 3830.018 85.5 384 0.028 88.0 22 385 0.068 72.5 11 386 0.009 97.8 39 3870.042 95.5 388 0.052 89.0 389 0.038 85.5 390 0.014 88.0 391 0.008 97.0392 0.006 100.0 393 0.125 100.0 394 0.007 100.0 395 0.007 100.0 3960.017 92.0 29 397 0.032 90.0 398 0.010 100.0 26 399 0.040 96.5 11 4000.005 100.0 32 401 0.041 95.5 402 0.025 97.5 18 403 0.032 100.0 4040.007 98.3 35 405 0.008 95.5 406 0.009 88.0 407 0.007 98.5 32 408 0.00994.0 409 0.019 99.5 22 410 0.009 87.0 36 411 0.021 100.0 412 0.016 98.034 413 0.010 100.0 414 0.009 100.0 40 415 0.006 96.0 416 0.008 92.0 4170.024 100.0 418 0.017 89.0 7 419 0.046 91.5 420 0.016 97.5 421 0.048100.0 422 0.006 79.0 16 423 3.150 53.5 424 0.007 99.0 15 425 0.005 90.59 426 0.048 92.0 427 0.019 91.5 428 0.072 86.0 429 0.016 99.0 430 0.06190.0 431 0.092 98.0 432 0.040 94.0 26 433 0.170 100.0 434 0.061 92.0 4350.084 100.0 436 0.081 94.0 437 0.009 98.4 29 438 0.037 99.5 439 0.020100.0 35 440 0.023 98.5 441 0.015 100.0 442 0.010 100.0 443 0.009 100.0444 0.051 100.0 445 0.096 97.5 446 0.050 85.0 21 447 0.024 93.0 4480.019 97.0 22 449 0.015 91.0 34 450 0.019 78.5 451 0.008 91.0 21 4520.013 100.0 25 453 0.011 98.5 454 0.007 100.0 28 455 0.010 100.0 17 4560.009 92.0 32 457 0.004 82.0 36 458 0.003 100.0 459 0.004 95.0 460 0.00598.0 461 0.039 89.0 462 0.018 88.0 17 463 0.054 89.0 464 0.128 82.5 4650.076 89.0 466 0.026 100.0 467 0.042 97.5 468 0.023 98.5 469 0.020 100.0470 0.104 98.5 471 0.010 89.0 472 0.029 90.0 473 0.031 100.0 474 0.005100.0 44 475 0.002 100.0 68 476 0.018 98.0 477 0.073 89.0 478 0.024100.0 479 0.038 100.0 480 0.046 100.0 481 0.010 100.0 482 0.013 98.5 4830.054 92.5 484 0.006 99.5 44 485 0.006 100.0 486 0.004 100.0 487 0.01296.5 488 0.024 96.0 53 489 0.027 100.0 23 490 0.103 91.5 491 0.106 85.5492 0.044 97.5 493 0.016 94.5 14 494 0.028 78.0 20 495 0.031 99.5 4960.067 89.0 497 0.029 92.0 498 0.060 83.5 499 0.063 96.0 500 0.076 100.0501 0.058 98.0 502 0.030 91.0 503 0.028 88.5 24 504 0.004 100.0 47 5050.006 100.0 506 0.007 100.0 57 507 0.006 98.0 37 508 0.007 93.5 5090.007 88.0 510 0.006 94.0 46 511 0.009 100.0 30 512 0.010 100.0 5130.010 91.0 514 0.010 99.0 30 515 0.012 99.3 37 516 0.020 100.0 35 5170.085 88.5 518 0.470 99.5 519 0.003 96.7 520 0.002 100.0 36 521 0.002100.0 72 522 0.004 92.8 523 0.001 100.0 41 524 0.002 100.0 60 525 0.005100.0 526 0.009 100.0 527 0.005 100.0 61 528 0.006 100.0 66 529 0.00696.0 530 0.006 98.7 44 531 0.009 97.0 532 0.018 92.0 533 0.024 100.0 5340.006 100.0 535 0.007 100.0 27 536 0.016 99.5 537 0.010 92.0 31 5380.007 100.0 40 539 0.007 86.5 21 540 0.009 90.0 541 0.007 92.2 31 5420.019 98.5 36 543 0.008 100.0 28 544 0.008 98.0 545 0.008 99.0 546 0.010100.0 547 0.120 90.0 548 0.009 100.0 37 549 0.009 100.0 550 0.009 100.034 551 0.018 100.0 552 0.014 96.0 553 0.013 97.5 49 554 0.010 94.5 54555 0.010 100.0 556 0.010 100.0 557 0.011 100.0 44 558 0.022 100.0 5590.010 99.0 560 0.017 100.0 561 0.004 95.0 62 562 0.010 100.0 40 5630.020 100.0 564 0.042 89.0 565 0.010 99.5 566 0.016 96.5 567 0.140 80.0568 0.011 100.0 569 0.049 100.0 570 0.056 100.0 571 0.012 94.0 33 5720.012 100.0 573 0.012 100.0 57 574 0.012 100.0 36 575 0.013 96.0 5760.013 99.5 577 0.020 100.0 578 0.017 100.0 29 579 0.014 97.5 580 0.014100.0 581 0.014 98.0 582 0.014 100.0 583 0.019 100.0 584 0.016 98.0 5850.014 95.5 586 0.015 100.0 587 0.014 93.5 588 0.009 100.0 589 0.015100.0 34 590 0.015 100.0 43 591 0.016 100.0 592 0.016 99.5 593 0.01789.5 29 594 0.018 100.0 595 0.019 94.0 36 596 0.021 98.5 19 597 0.02195.5 598 0.021 100.0 599 0.023 90.0 600 0.028 96.9 601 0.073 100.0 6020.023 91.5 603 0.025 89.5 604 0.025 93.5 605 0.025 98.0 606 0.027 98.0607 0.005 100.0 32 608 0.022 100.0 609 0.028 99.0 610 0.011 100.0 6110.017 90.0 612 0.029 100.0 613 0.033 95.5 614 0.036 94.5 615 0.053 99.3616 0.037 90.5 617 0.096 98.0 618 0.039 99.0 30 619 0.040 88.6 620 0.047100.0 621 0.010 100.0 44 622 0.043 93.0 623 0.067 97.0 624 0.140 96.5625 0.043 100.0 626 0.044 93.5 627 0.140 83.5 628 0.032 89.5 629 0.044100.0 630 0.048 100.0 631 0.049 86.0 23 632 0.049 100.0 633 0.052 93.8634 0.054 100.0 48 635 0.059 100.0 636 0.060 98.1 637 0.060 93.0 6380.063 100.0 639 0.068 96.5 25 640 0.069 91.3 641 0.071 100.0 642 0.072100.0 643 0.073 92.0 644 0.074 85.0 645 0.074 83.0 646 0.074 100.0 30647 0.077 92.0 648 0.081 96.5 49 649 0.083 94.0 650 0.083 100.0 6510.086 95.0 652 0.089 80.0 653 0.089 86.5 654 0.093 84.0 655 0.097 98.0656 0.100 91.5 657 0.100 85.3 658 0.006 100.0 659 0.081 98.0 660 0.10284.5 661 0.048 95.5 662 0.038 100.0 663 0.030 90.5 664 0.100 98.0 6650.073 92.5 666 0.022 100.0 60 667 3.850 100.0 668 0.089 100.0 669 0.10684.9 670 1.450 66.5 671 0.100 94.0

B-2. Functional Ca2+ Release Test by Means of M2-Gα16 Reporter Cells

Any potentially agonistic or else potentially allosteric effect of thetest substances on the M2 receptor can be determined by a functionalCa2+ release test. The activation of the M2 receptor by binding oforthosteric agonists (acetylcholine) or other substances having anagonistic effect leads to a change in conformation of the receptor,which, in the endogenous state, results in Gαi protein activation.However, coupling of the M2 receptor to the exogenously expressedpromiscuous Gαq protein Gα16 results in Gα16 protein activation afteractivation of the M2 receptor, which causes—via a downstream signaltransduction cascade—intracellular Ca²⁺ release. The extent ofintracellular Ca²⁺ mobilization can therefore be regarded as a measureof the activation of the M2 receptor.

The test cell used is a recombinant CHO cell line which has been stablytransfected with cDNA coding for the human M2 receptor and the Gα16protein and with cDNA coding for the mitochondrially expressedphotoprotein clytin (mtClytin) (CHO mtClytin Gα16 M2). The determinationof the intracellular Ca²⁺ release as a function of substance addition orM2 activation is effected by means of a Ca²⁺-sensitive dye (Fluo-8) andthe measurement of cell fluorescence using a FLIPR^(TETRA) instrument(Molecular Devices).

B-2.1. Agonism Assay

The test substances are dissolved in DMSO at a concentration of 10 mMand serially diluted with DMSO in steps of 1:3.16 for a 10-pointdose/activity analysis. In accordance with the desired testconcentrations, the substances are prediluted in Fluo-8 buffer(composition per 100 ml: 500 μl probenecid, 2 ml Brilliant Black (20mg/ml), 440 μl Fluo-8, 2 mM CaCl₂ ad 100 ml CAFTY Tyrode (130 mM NaCl, 5mM KCl, 20 mM HEPES, 1 mM MgCl₂, 5 mM NaHCO₃, pH 7.4)).

The reporter cells cultivated in MEM alpha medium (supplemented with 10%FCS, 2% Glutamax) were sown with 3000 cells in 30 μl of sowing mediumper 384-well in μCLEAR/schwarz Greiner cell culture plates (#781092) andincubated at 37° C. for 24 h. The sowing medium consists of MEM alphamedium (supplemented with 5% FCS, 2% Glutamax). For the respectivemeasurement, the medium is removed and the cells, after addition of 20μl in each case of Fluo-8 buffer per 384-well, were incubated in anincubator at 37° C. for 1 h. After addition of 10 μl in each case per384-well of the prediluted test substances, cell fluorescence wasmeasured for a period of 5 min in 1 sec increments. The relative degreeof maximum activation of the M2 receptor by the respective testsubstances is calculated by normalizing the test signal to the signalcorresponding to the E_(Max) concentration of acetylcholine (3 μM).

B-2.2. Determination of the Positive Allosteric Modulator Effect

In order to be able to determine the positive cooperativity of the testsubstances in relation to the acetylcholine-mediated M2 receptoractivation, reference agonist (acetylcholine) is then added for a fulldose-response analysis. For this purpose, acetylcholine is seriallydiluted in Fluo-8 buffer in steps of 1:3.16 beginning with a maximumfinal concentration of 1 μM. After addition of 10 μl in each case ofagonist solution per 384-well, cell fluorescence is again measured for aperiod of 5 min in 1 sec increments. The same assay plate is used asimmediately before for the M2 agonism assay. The shift in theacetylcholine dose-response curve in the presence of increasingconcentrations of the test substance is analysed and quantified by meansof GraphPad PRISM (Allosteric EC₅₀ shift) (see above).

B-3. Selectivity Test with Respect to Human Muscarinic AcetylcholineReceptors

Any potentially agonistic effect, or else positive allosteric effect, ofthe test substances on other human muscarinic acetylcholine receptorscan be determined in a functional Ca²⁺ release test (Eurofins;GPCRProfiler® Services in agonistic and allosteric mode for MxReceptors; cat#: HTS600GPCR).

The test cells used were the Chem-1 or Chem-4 cell lines transfectedwith the particular receptor (ChemiScreen™ M1 Calcium-Optimized FLIPRCell Lines, Eurofins; M1: HTS044C; ChemiScreen™ Calcium-Optimized StableCell Line Human Recombinant M2 Muscarininc Acetylcholine Receptor,Eurofins; M2: HTS115C; ChemiScreen™ Human Recombinant M3 MuscarinicAcetylcholine Receptor Calcium-Optimized Stable Cell Line, Eurofins; M3:HTS116C; ChemiScreen™ Human Recombinant M4 Muscarinic AcetylcholineReceptor Calcium-Optimized Stable Cell Line, Eurofins; M4: HTS117C;ChemiScreen™ M5 Calcium-Optimized FLIPR Cell Lines, Eurofins; M5:HTS075C). The substance test is conducted with a FLIPR^(TETRA)instrument (Molecular Devices).

B-3.1. Agonism Assay

In order to determine any potential agonistic effect of the testsubstances, the respective test substances were added with a final testconcentration of 10 μM or 1 μM. Ca²⁺ release or cell fluorescence ismeasured over a period of 180 sec. The positive control used fornormalization of the substance effect to the receptor activation is aconcentration of acetylcholine corresponding to the E_(Max) value.

After the agonism assay has ended, the assay plate is incubated at 25°C. for 7 min. After the incubation period, the positive allostericmodulator assay is initialized.

B-3.2. Allosteric Modulator Assay

In order to examine any positive or negative allosteric effect of thetest substances on other human muscarinic acetylcholine receptors andthe M2 receptor itself, every substance concentration is combined withan acetylcholine 8-point dose-response curve. Addition of agonistsolution is again followed in turn by the measurement of cellfluorescence for a period of 180 sec. The shift in the acetylcholinedose-response curve (maximum shift in the EC₅₀ of acetylcholine) isanalysed and quantified by means of GraphPad PRISM (Sigmoidaldose-response (variable slope)−EC₅₀). Finally, quotients of theallosteric shift for the M2 receptor and M4 receptor are formed, whichfunction in turn as a measure of the respective selectivity.

Tables 2 and 3 below list, for individual working examples, thequotients thus determined using selected molecules from this assay:

TABLE 2 Selectivity EC₅₀ EC₅₀ (Shift EC₅₀ ACh M2 ACh M4 ConcentrationShift Shift M2/Shift Ex. No. [nM] [nM] [μM] EC₅₀ M2 EC₅₀ M4 EC₅₀ M4)Ref. 440 100 10 46 56 0.8 (LY2119620) Ref. 440 100 1 24 83 0.3(LY2119620) 175 440 100 10 76 0.9 83 175 440 100 1 21 0.7 29 323 323 11010 40 0.9 44 323 350 110 1 48 0.9 52 590 350 110 10 39 1.2 33 590 350110 1 7 1.1 7

More particularly, it is clear from Table 2 that the selectivity of theabove-addressed molecule LY2119620 has a clear tendency in favour of M4,whereas the selectivity of the molecules according to the invention isbalanced or biased to M2.

TABLE 3 Selectivity EC₅₀ EC₅₀ (Shift EC₅₀ ACh M2 ACh M4 ConcentrationShift Shift M2/Shift Ex. No. [nM] [nM] [μM] EC₅₀ M2 EC₅₀ M1 EC₅₀ M1)Ref. 18 100 10 46 11 4 (LY2119620) 175 18 100 10 76 0.3 287 323 18 10010 40 1.3 31 590 18 100 10 39 1.3 30

It is clear from Table 3 that the molecules according to the inventionhave a very much greater selectivity for M2 compared to M1 than theabove-addressed molecule LY2119620.

B-4. In Vitro M2 PAM Gi Assay

For the characterization of the test substances on positive allostericmodulation of the human M2 receptor, the carbachol-induced inhibition ofthe rise in cAMP due to forskolin in recombinant M2 receptor-expressingCHO cells is measured, these additionally expressing a luciferase geneunder the control of a cAMP-responsive element (CRE): 3000 cells in 25μl of full medium (DMEM F12 PAN medium, 10% FCS, 1.35 mM Na pyruvate, 20mM Hepes, 4 mM Glutamax, 2% sodium bicarbonate, 1% Pen/Strep, 1% 100×nonessential amino acids) are sown per well of a 384 multititre plate(Greiner, TC Platte, black with clear base) and incubated at 37° C., 5%CO₂ for 24 hours. Before the measurement, the medium is replaced by 30μl of test medium (Optimem) and incubated at 37° C., 5% CO₂ for 10minutes. The test substance is prepared in DMSO in variousconcentrations (starting concentration 10 mM, dilution factor 3.16) as adose-response curve and pre-diluted 1:50 with calcium-free Tyrode, 2 mMCaCl₂, 0.01% BSA. 10 μl of the pre-diluted substance solution are addedto the cells and incubated at 37° C., 5% CO₂ for 10 minutes. The M2receptor is activated by adding 10 μl of carbachol in variousconcentrations in calcium-free Tyrode, 2 mM CaCl₂ and incubated at 37°C., 5% CO₂ for 5 minutes. Adenylyl cyclase is activated by adding 10 μlof 1 μM (final concentration) forskolin in calcium-free Tyrode, 2 mMCaCl₂ and incubated at 37° C., 5% CO₂ for 5 hours.

After removing the cell supernatant and adding 20 μl of Luci/Tritonbuffer (1:1), luminescence is determined in a luminometer for 60seconds.

Calcium-free Tyrode: 130 mM NaCl, 5 mM KCl, 20 mM HEPES, 1 mM MgCl₂, 4.8mM NaHCO₃, pH 7.4

Luci/Triton buffer (1:1): Luci buffer (20 mM tricine, pH 7.8, 2.67 mMmagnesium sulphate, 0.1 mM EDTA, 4 mM DTT, 270 μM coenzyme A, 470 μMD-luciferin, 530 μM ATP) mixed 1:1 with triton buffer (25 mM Trisaqueous hydrochloric acid, pH 7.8, 25 mM Na₂HPO₄, 2 mM dithiothreitol,3% Triton X-100, 10% glycerin).

The EC₅₀ value was determined with the aid of a 4-parameter logisticfunction (Hill function).

B-5. Competitive Binding Test for Human M2 and M4 Receptors

The direct binding of the test substances to the M2 receptor and theboosting of the binding (increasing affinity) of the natural agonistacetylcholine to the M2 receptor in the presence of the test substances(positive allosteric effect) is determined by means of a FRET-basedbinding assay (HTRF Tag-Lite® binding assay, Cisbio). For control ofselectivity, the binding of the test substances to the structurallyrelated M4 receptor is examined analogously. The HTRF Tag-Lite® assay isa homogeneous binding assay and is based on the competitive binding of afluorescent ligand (probe) and the unlabelled test substance to thereceptor, which is expressed in living cells. The receptor in turn isderivatized with a fluorescent donor dye (terbium cryptate), such thatexcitation of the donor dye gives rise to a FRET signal between thereceptor and probe (acceptor) when the probe is bound to the receptor.The acceptor probe used was a telenzepine derivative conjugated with anHTRF fluorescent dye (red ligand; L0040RED). The probe therefore bindsin the conserved orthosteric binding site both of the M2 and of the M4receptor. The allosteric binding site of the M2 receptor has beencharacterized by x-ray crystallography and is postulated as beingdirectly above the orthosteric binding pocket (Kruse et al., Nature,2013, 504, 101-106). Both the binding of unlabelled orthosteric agonists(acetylcholine) to the orthosteric binding site and the binding ofallosteric modulators (test substances) to the allosteric binding sitetherefore leads to a concentration-dependent competitive displacement ofthe probe and hence to a decrease in the FRET-based fluorescence signal.

All binding tests are conducted on white 384 microtitre plates (smallvolume) in a total volume of 20 μl. The HTRF measurements are undertakenwith a PHERAstar instrument (BMG Labtech). For the muscarinic M2 or M4receptor binding test, SNAPed-M2-expressing cells (C1TT1M2) orSNAPed-M4-expressing cells (C1TT1M4) are used, which have been labelledwith a donor fluorophore (Lumi4Tb; CELLCUST). The cells are incubatedwith the acceptor probe in Tag-lite binding buffer (LABMED) in thepresence of test substance or acetylcholine. Subsequently, thefluorescence signal is measured at wavelengths of 665 nm and 620 nm andthe HTRF quotient (signal at 665 nm/signal at 620 nm) is determined. Therelative specific signal is determined by subtracting the HTRF quotientof negative control (Tag-lite buffer only without probe).

B-5.1. Binding of the Test Substances

In order to determine the binding of the test substances to the M2 or M4receptor in the absence of orthosteric agonist, a dose-response analysisof the test substances is undertaken in the competitive format of theM2-Tag-Lite® or M4-Tag-Lite® binding assay. The test substances aredissolved in DMSO at a concentration of 10 mM and serially diluted withDMSO in steps of 1:3.16 for a dose-response analysis. The maximum testconcentration corresponds to 10 μM. The molar concentration of the testsubstance that brought about a half-maximum reduction in the HTRF signalin relation to the maximum and remaining HTRF signal at the highestsubstance concentration (EC₅₀ of the binding) is determined by means ofGraphPad PRISM (Sigmoidal dose response). At the same time, the strengthof the competition effect is determined by calculating the maximumdecrease in the specific HTRF signal at the highest substanceconcentration (% max. competition).

B-5.2. Binding of the Test Substances in Allosteric Mode

To examine the allosteric modulation of the M2 receptor by the testcompounds, firstly, a dose-response analysis of the test substances inthe competitive format of the M2-Tag-Lite® or M4-Tag-Lite® binding assayin the presence of a concentration of acetylcholine corresponding to theEC₂₀ value is undertaken, the latter being determined in a separate11-point acetylcholine dose-response analysis (3 μM). The testsubstances are dissolved in DMSO at a concentration of 10 mM andserially diluted with DMSO in steps of 1:3.16 for a 10-pointdose/activity analysis. The maximum test concentration corresponds to 10μM. The molar concentration of the test substance that brought about ahalf-maximum reduction in the HTRF signal in relation to the maximum andremaining HTRF signal at the highest substance concentration in thepresence of an acetylcholine concentration corresponding to the EC20value (EC₅₀ of the binding) is determined by means of GraphPad PRISM(Sigmoidal dose response). At the same time, the strength of thecompetition effect is determined by calculating the maximum decrease inthe specific HTRF signal at the highest substance concentration (% max.competition).

In order to examine the boosting of the binding of acetylcholine to theM2 or M4 receptor, in addition, secondly, an 11-point dose-responseanalysis of acetylcholine in the competitive format of the M2-Tag-Lite®or M4-Tag-Lite® binding assay was undertaken in the absence or in thepresence of 1 μM or 10 μM test substance. The shift in the acetylcholinedose-response curve (maximum shift in the EC50 value of acetylcholine)was analysed and quantified by means of GraphPad PRISM (Sigmoidaldose-response).

B-6. Radioliand Binding Assay for Human M2 Receptors

The allosteric mechanism of action of the test substances can be furtherinvestigated in detail and be quantified by various radioligand bindingassays. The binding of the allostere to the allosteric binding site ofthe M2 receptor results in an increase in the binding affinity of theorthosteric ligand for the M2 receptor in the case of positivecooperativity. The increase in the binding affinity of the orthostericligand by the allostere in the ternary complex consisting of orthostere,allostere and M2 receptor is in turn due to modulation of the bindingkinetics of the orthostere. The allostere can alter the associationand/or dissociation rate of the orthostere at the M2 receptor. Alowering of the dissociation rate reflects in this case a stabilizationof the ternary complex and accompanies therefore a lowering of thedissociation constant of the orthosteric ligand under equilibriumconditions (Lazareno, Determination of Allosteric Interactions UsingRadioligand-Binding Techniques in Methods in Molecular Biology, vol.259, Receptor Signal Transduction Protocols, 2nd ed.; Kostenis and Mohr,Trends Pharmacol. Sci. 1996, 17(8), 280-283).

B-6.1. Radioligand Binding Assay Under Equilibrium Conditions

In order to check and to quantify the influence of the test substanceson the binding affinity of orthosteric agonists for the M2 receptor, aradioligand binding assay under equilibrium conditions can be conducted.In this case, the binding of the radiolabelled M2 receptor agonist³H-oxotremorine M to the M2 receptor is investigated at differentconcentrations of ³H-oxotremorine M in the binding equilibrium (Croy etal., Mol. Pharmacol. 2014, 86, 106-115). Based on the amount ofradioactive agonist specifically bound to the M2 receptor as a functionof the agonist concentration (graphically represented as the so-calledLangmuir isotherm), firstly the equilibrium dissociation constant K_(d)of the agonist can be calculated as a quantitative measure of itsbinding affinity for the M2 receptor and secondly the concentration ornumber of specific binding sites of the radioligand (agonist) B_(max) inthe absence or presence of different concentrations of the testsubstances (positive allosteric modulators) (Hulme and Trevethick, Brit.J. Pharmacol. 2010, 161, 1219-1237).

The radioligand binding assay for the M2 receptor (Euroscreen,FAST-0261B) is carried out by means of ³H-labelled oxotremorine M(NET671) as agonist. The agonist binding to the M2 receptor is carriedout in triplicate on 96-well microtitre plates (Master Block, Greiner,786201) in binding buffer (sodium/potassium phosphate buffer, pH 7.4).For this purpose, each assay of M2 membrane extracts (20 μg ofprotein/96 well) are incubated with various concentrations ofradiolabelled agonists (0.2-100 nM) alone or in the presence of 1 μM or10 μM test substance or binding buffer alone in a total volume of 0.1 mLat 37° C. for 60 min. The non-specific binding of ³H-labelledoxotremorine M to the membrane is determined by co-incubating withN-methylscopolamine (NMS), an orthosteric antagonist of the M2 receptor,in a 200-fold excess. In order to stop the binding reaction, the samplesare then filtered via GF/C filter (Perkin Elmer, 6005174), which hadpreviously been wetted with 0.5% polyethylenimine (PEI) solution, for 2h at room temperature. The filters are washed six times each with 0.5 mLof ice-cold wash buffer (10 mM sodium/potassium phosphate buffer, pH7.4) and 50 μL of Microscint 20 scintillation solution (Packard) addedper assay. The samples are then incubated for 15 min on an orbitalshaker before the radioactivity is measured by means of a TopCount™instrument (1 min/well).

The test substances are dissolved in DMSO at a concentration of 10 mMand further diluted in DMSO corresponding to the final testconcentration in order to obtain a 100-fold dilution of the DMSOsolution used in binding buffer.

The K_(d) and B_(max) of ³H-oxotremorine M for the M2 receptor aredetermined with the aid of a “one-site” specific binding model (Croy etal., Mol. Pharmacol. 2014, 86, 106-115).

B-6.2. Competitive Radioligand Binding Assay Under EquilibriumConditions

In order to check and to quantify further the influence of the testsubstances on the binding affinity of orthosteric agonists for the M2receptor, a competitive radioligand binding assay under equilibriumconditions is also conducted. In this case, the binding of theantagonistic radioligand ³H-N-methylscopolamine (³H-NMS) to the M2receptor is determined in the absence or presence of variousconcentrations of non-radiolabelled agonist oxotremorine M (Croy et al.,Mol. Pharmacol. 2014, 86, 106-115; Schober et al., Mol. Pharmacol. 2014,86, 116-123). The radiolabelled probe (antagonist) and the non-labelledagonist compete for the binding to the orthosteric binding site of theM2 receptor. The ability to displace the radiolabelled probe thereforeserves as a measure of the binding affinity of the agonist for thereceptor and can be quantified in accordance with the Cheng-Prusoffequation as an equilibrium inhibition constant (K_(i)) (Cheng andPrusoff, Biochem. Pharmacol. 1973, 22(23), 3099-3108). In order tofurther investigate the allosteric effect of the test substances, theinfluence of the test substances on the K_(i) of oxotremorine M isdetermined.

The antagonist inhibition binding assay for the M2 receptor (Euroscreen,FAST-0261B) is carried out on 96-well microtitre plates (Master Block,Greiner, 786201) in binding buffer (50 mM Tris buffer pH 7.4, 1 mM EDTA,10 μg/ml saponin) using ³H-NMS as M2 receptor antagonist. To adjust thebinding equilibrium, each assay of M2 membrane extracts (20 μg ofprotein/96 well) are incubated with a defined concentration ofradiolabelled antagonist (0.5 nM) alone or in the presence of variousconcentrations of non-labelled agonists (oxotremorine M; 0.001 nM to 1mM) with or without 1 μM or 10 μM test substance or binding buffer alonein a total volume of 0.1 mL at 25° C. for 2 h. The non-specific bindingof ³H-labelled NMS to the membrane is determined by co-incubating withnon-radiolabelled acetylcholine in a 200-fold excess. In order to stopthe binding reaction, the samples are then filtered over GF/C filters(Perkin Elmer, 6005174), which had previously been wetted with 0.5% PEIsolution, for 2 h at room temperature. The filters are washed six timeseach with 0.5 mL of ice-cold wash buffer (10 mM sodium/potassiumphosphate buffer, pH 7.4) and 50 μL of Microscint 20 scintillationsolution (Packard) is added per assay. The samples were then incubatedfor 15 min on an orbital shaker before the radioactivity is measured bymeans of a TopCount™ instrument (1 min/well).

The test substances are dissolved in DMSO at a concentration of 10 mMand further diluted in DMSO corresponding to the final testconcentration in order to obtain a 100-fold dilution of the DMSOsolution used in binding buffer.

The K_(i) values in the presence or absence of test substance arequantified with the aid of the Cheng-Prusoff equation (Cheng andPrusoff, Biochem. Pharmacol. 1973, 22(23), 3099-3108). In this case, theIC₅₀ values of the substances are determined according to a fourparameter logistic equation and the K_(d) of NMS determined in aradioligand binding assay under equilibrium conditions (Schober et al.,Mol. Pharmacol. 2014, 86, 116-123).

B-6.3. Kinetic Radioligand Binding Assay

By means of a kinetic radioligand binding assay, the kinetics of thedissociation of the radiolabelled agonist ³H-oxotremorine M for the M2receptor in the presence or absence of test substance can beinvestigated. By these means, the influence of the allosteric activityof the test substances on the dissociation constant (k_(off) rate) ofthe M2 agonist can be determined and thus the allosteric mechanism ofthe test substances can be further characterized (Lazareno,Determination of Allosteric Interactions Using Radioligand-BindingTechniques in Methods in Molecular Biology, vol. 259, Receptor SignalTransduction Protocols, 2nd ed.; Schrage et al.).

The radioligand dissociation binding assay for the M2 receptor(Euroscreen, FAST-0261B) is carried out with ³H-labelled oxotremorine M(NET671) as agonist. The binding reaction is carried out in bindingbuffer (sodium/potassium phosphate buffer, pH 7.4) on 96-well microtitreplates (Master Block, Greiner, 786201). For this purpose, each assay ofM2 membrane extracts (20 μg of protein/96 well) are pre-incubated with adefined concentration of radiolabelled agonist (9.65 nM) alone or in thepresence of 1 μM or 10 μM test substance or binding buffer alone at 37°C. for 60 min. NMS is then added in 200-fold excess at various timepoints (one time point per assay) and the mixtures incubated in a totalvolume of 0.1 mL at 37° C. In order to stop the binding reaction, thesamples are then filtered over GF/C filters (Perkin Elmer, 6005174),which had previously been wetted with 0.5% PEI solution, for 2 h at roomtemperature. The filters are washed six times each with 0.5 mL ofice-cold wash buffer (10 mM sodium/potassium phosphate buffer, pH 7.4)and 50 μL of Microscint 20 scintillation solution (Packard) is added perassay. The samples are then incubated for 15 min on an orbital shakerbefore the radioactivity is measured by means of a TopCount™ instrument(1 min/well).

The test substances are dissolved in DMSO at a concentration of 10 mMand further diluted in DMSO corresponding to the final testconcentration in order to obtain a 100-fold dilution of the DMSOsolution used in binding buffer.

The k_(off) was determined with the aid of a “one phase” exponentialdecay model of the dissociation (Hulme and Trevethick, Brit. J.Pharmacol. 2010, 161, 1219-1237; Kostenis and Mohr, Trends Pharmacol.Sci. 1996, 17(8), 280-283).

B-7. Effects of the Test Substances on Acetylcholine-Mediated GIRK1/4Channel Currents in Primary Atrial Rat Cardiomyocytes

The substance testing is carried out in accordance with a patch clampprotocol described in the literature for the electrophysiologicalmeasurement of acetylcholine-induced GIRK1/4 membrane currents in nativerat atrial myocytes (see e.g. Beckmann and Rinne et al., GProtein-Activated (GIRK) Current in Rat Ventricular Myocytes is Maskedby Constitutive Inward Rectifier Current (IK1), Cell Physiol Biochem2008; 21:259-268).

An acetylcholine dose-response curve for GIRK1/4 activity is initiallydetermined in the absence of test substance (DMSO control) by perfusingtest solutions with increasing acetylcholine concentration and measuringthe resulting membrane currents. The membrane currents or change in themembrane currents are measured for a given ACh concentration for approx.10 to 20 seconds. After application of the maximum ACh concentrationwithin a DRC series, a solution of atropine (10 μM) is perfused followedby washing out of the substance solutions in order to ensure the M2selectivity and reversibility of M2 activation. Changes of the membranecurrents are appropriately recorded. Here, each acetylcholineconcentration of the membrane current measured is in each casenormalized to the maximum acetylcholine-induced membrane current(I/IMax). An acetylcholine dose-response curve comprises in this casefive different concentrations (1 nM, 10 nM, 100 nM, 1 μM, 10 μM). TheEC50 value is determined with the aid of a 4-parameter logistic function(Hill function).

In order to determine the allosteric effect of the test substances onthe M2 receptor, the acetylcholine dose-response curve is determined forthe GIRK1/4 membrane current in the presence of a constant concentrationof the respective test substance (e.g. 1 μM). For this purpose, afterpre-incubation of the cell with the test substance for approx. 20seconds and measurement of the membrane currents, a test solutioncomprising the same substance concentration and a defined AChconcentration is perfused for approx. 10 to 20 seconds and the membranecurrents are measured. After application of the maximum acetylcholineconcentration within a measurement series, the perfusion of a solutionwith atropine (10 μM) is in turn carried out in order to check the M2selectivity of the substance effect. The EC50 value in the presence oftest substance is determined analogously with the aid of a 4-parameterlogistic function (Hill function) (see above).

The shift in the acetylcholine dose-response curve is determined andquantified by the change in the EC50 value for acetylcholine in theabsence or presence of the test substance.

B-8. Effects of the Test Substances on Isolated Perfused Rat Heart

Male Wistar rats (strain: (HsdCpb:WU) with a body weight of 200-250 gare anaesthetized with Narcoren (100 mg/kg). The thorax is opened andthe heart is then exposed, excised and connected to a Langendorffapparatus by placing a cannula into the aorta. The heart is perfusedretrogradely at 9 ml/min at constant flow with a Krebs-Henseleit buffersolution (gassed with 95% O₂ and 5% CO₂, pH 7.4, 35° C.; with thefollowing composition in mmol/l: NaCl 118; KCl 3; NaHCO₃ 22; KH₂PO₄ 1.2;magnesium sulphate 1.2; CaCl₂ 1.8; glucose 10; Na pyruvate 2). Tomeasure the contractility of the heart, a balloon, made of thin plasticfilm, which is attached to a PE tube and filled with water is introducedvia an opening in the left auricle of the heart into the left ventricle.The balloon is connected to a pressure transducer. The end-diastolicpressure is adjusted to 5-10 mmHg via the balloon volume. The data areenhanced by a bridge amplifier and registered on a computer using theLabChart software (ADInstruments).

To investigate the allosteric effect of the test substances, the heartsare perfused with addition of 300 nmol/l of the test substance. After 15min, carbachol is added cumulatively to the perfusion solution inincreasing concentrations. Lowering of the heart rate resultingtherefrom is compared, as dose-response curve, with effects on heartswhich had been treated with solvent in place of test substance. Theshift in the carbachol dose-response curve is analysed and quantified byGraphPad PRISM (sigmoidal dose-response).

B-9. Effects of the Test Substances on the Heart Rate in AnaesthetizedRats

Male rats of the strain (WI) WU Br from the breeder Charles River areanaesthetized initially with a 4-5% isoflurane inhalation for approx. 3min. Subsequently, anaesthesia is maintained using a 1.5% isofluraneinhalation. For this purpose, the anaesthetized animals are fixed on aheated operating plate. By means of visual inspection and between toereflex, the depth of anaesthesia is checked.

For the application of the test substance, an i.v. route into thejugular vein is used. A caudal to cranial skin incision is then madelongitudinally and both the cervical musculature and the salivary glandsare severed. The right common carotid artery is exposed and blood supplyis arrested both proximally and distally. Using microinstrumentation, aTIP catheter (1.2 F) is introduced into the vessel in order to measurethe arterial pressure and the heart rate.

Initially, both parameters are monitored for 10 min in the basal statewithout substance addition. The substances to be investigated aredissolved in suitable solvent mixtures and subsequently administered atvarious dosages to a group of animals in each case via the jugular veinby an infusion pump over 5 min. A solvent-treated group is used ascontrol under the same experimental conditions. The arterial bloodpressure and heart rate with substance addition is determined for 20min. The data are registered with the PowerLab system (AD instruments)and evaluated using the LabChart program (AD instruments).

The values determined in this manner for the percentage decrease inheart rate for individual working examples are given in Table 4 below(in some cases as means of a plurality of independent individualdeterminations):

TABLE 4 Reduction in Ex. No. heart rate (%) 28 9 174 7 175 6 189 7 201 6212 11 213 14 271 8 275 9 284 11 296 11 297 10 323 13 325 13 330 9 33211 342 10 349 14 370 12 386 13 400 11 404 9 407 13 414 16 511 10 520 15523 15 530 13 541 14 550 13 590 13

B-10. Radiotelemetric Measurement of Blood Pressure and Heart Rate ofConscious Rats

A commercially available telemetry system from Data SciencesInternational DSI, USA, is employed for the measurements on consciousrats described below. The system consists of 3 main components: (1)implantable transmitters (PhysioTel® telemetry transmitter), (2)receivers (PhysioTel® receiver), which are linked via a multiplexer (DSIData Exchange Matrix) to a (3) data acquisition computer. The telemetrysystem makes it possible to continuously record blood pressure, heartrate and body motion of conscious animals in their usual habitat.

The studies are conducted on adult female rats (Wistar Unilever/WU orSpontaneous Hypertensive Rat/SHR) with a body weight of >200 g. Aftertransmitter implantation, the experimental animals are housed singly intype III Makrolon® cages. They have free access to standard feed andwater. The day/night rhythm in the test laboratory is set by changingthe illumination of the room.

Transmitter Implantation:

The telemetry transmitters used (e.g. PA-C40 HD-S10, DSI) are surgicallyimplanted under aseptic conditions in the experimental animals at least14 days before the first experimental use. For the implantation, thefasted animals are anaesthetized with isoflurane (IsoFlo®, Abbott,initiation 5%, maintenance 2%) and shaved and disinfected over a largearea of their abdomens. After the abdominal cavity has been opened alongthe linea alba, the liquid-filled measuring catheter of the system isinserted into the descending aorta in the cranial direction above thebifurcation and fixed with tissue glue (Vetbond™, 3M). The transmitterhousing is fixed intraperitoneally to the abdominal wall muscle, and thewound is closed layer by layer. Post-operatively, an antibiotic(Ursocyclin® 10%, 60 mg/kg s.c., 0.06 ml/100 g body weight, SerumwerkBernburg AG, Germany) for infection prophylaxis and an analgesic(Rimadyl®, 4 mg/kg s.c., Pfizer, Germany) are administered.

Substances and Solutions:

Unless stated otherwise, the substances to be studied are administeredorally to a group of animals in each case (M=6). In accordance with anadministration volume of 2 ml/kg of body weight, the test substances aredissolved in suitable solvent mixtures. A solvent-treated group ofanimals is used as control.

Experimental Outline:

The telemetry measuring system is configured for 24 animals. Each of theinstrumented rats living in the system is assigned a separate receivingantenna (RPC-1 Receiver, DSI). The implanted senders can be activatedexternally via an installed magnetic switch and are switched totransmission during the pre-run of the experiment. The signals emittedcan be detected online by a data acquisition system (Dataquest™ A.R.T.for Windows, DSI or Ponemah, DSI) and processed accordingly. In thestandard procedure, the following are measured for 10-second periods ineach case: (1) systolic blood pressure (SBP), (2) diastolic bloodpressure (DBP), (3) mean arterial pressure (MAP), (4) heart rate (HR)and (5) activity (ACT). These parameters are measured over 24 hoursafter administration. The acquisition of measurements is repeated undercomputer control at 5-minute intervals. The source data obtained asabsolute values are corrected in the diagram with the currently measuredbarometric pressure (Ambient Pressure Reference Monitor, APR-1, DSI).

Evaluation:

After the end of the experiment, the acquired individual data are sortedusing the analysis software (Dataquest™ A.R.T. 4.1 Analysis or Ponemah,DSI). The 2 hour time point before substance application is assumed asthe blank value. The data are smoothed over a presettable period bydetermination of the means (30 minute mean).

B-11. Effects of the Test Substances on the Heart Rate in AnaesthetizedDogs

Male or female cross-breeds (Mongrels, Marshall BioResources, USA) witha body weight between 20 and 30 kg are anaesthetized with pentobarbital(30 mg/kg iv, Narcoren®, Merial, Germany). Pancuronium chloride(Pancuronium-Actavis®, Actavis, Germany, 1 mg/animal iv) serves hereadditionally as muscle relaxant. The dogs are intubated and ventilatedwith an oxygen-air mixture (40/60%) (approximately 5-6 L/min). Theventilation is conducted using a ventilation device from GE Healthcare(Avance), which also serves as anaesthesia monitor (C02 analyser). Theanaesthesia is maintained by a constant infusion of pentobarbital (50μg/kg/min); fentanyl (10 μg/kg/h) serves as analgesic. An alternative topentobarbital consists of using isoflurane (1-2% by volume).

The dog is provided with the following:

-   -   bladder catheter for bladder emptying or measurement of urine        flow    -   ECG leads to the extremities (for ECG measurement)    -   insertion of a NaCl-filled Fluidmedic-PE-300 loop into the A.        femoralis. This is linked to a pressure sensor (Braun Melsungen,        Melsungen, Germany) for measuring the systemic blood pressure    -   insertion of a NaCl-filled venous catheter (Vygon, Germany) into        the V. femoralis for infusing test substances or withdrawing        blood.    -   insertion of a Millar Tip catheter (Typ 350 PC, Millar        Instruments, Houston, USA) via the left atrium or via a sluice        for measuring the heart haemodynamics incorporated into the A.        carotis    -   insertion of a Swan-Ganz catheter (CCOmbo 7.5F, Edwards, Irvine,        USA) via the V. jugularis into the A. pulmonalis for measuring        cardiac output, oxygen saturation, pulmonary arterial pressures        and central venous pressure.    -   provision of an ultrasound flowmeter probe (Transsonic Systems,        Ithaka, USA) to the Aorta descendens for measuring aorta flow    -   provision of an ultrasound flowmeter probe (Transsonic Systems,        Ithaka, USA) to the left Aorta coronaria for measuring coronary        flow    -   placement of a Brauniile into the Venae cephalicae for infusing        pentobarbital, liquid substitution and for withdrawing blood        (determination of the substance plasma levels or other clinical        blood values)    -   placement of a Brauniile into the Venae saphenae for infusing        fentanyl and substance application

The primary signals are possibly amplified (Gould Amplifier, GouldInstrument Systems, Valley View, USA) or Edwards Vigilance Monitor(Edwards, Irvine, USA) and subsequently fed into the Ponemah system(DataSciences Inc, Minneapolis, USA) for evaluation. The signals arerecorded continuously over the whole experimental time course, furtherprocessed digitally by this software and averaged over 30 s.

B-12. Effects of the Test Substances on the Heart Rate and Heart RateVariability in Healthy, Conscious Dogs

To characterize test substances with regard to their effect on heartrate, heart rate variability (HRV) and blood pressure, telemetricmeasurements are conducted in healthy, male Beagle dogs. Underisoflurane anaesthesia, a telemetry transmitter (model L21, from DataSciences International, USA) is firstly implanted in the animals. Afterleft-sided thoracotomy, pressure sensors are then placed in the aortaand in the left ventricle. To record an electrocardiogram (ECG), furtherelectrodes are placed on the heart. For wound healing, the animals arethen placed back in the pen under antiobiotic (clindamycin, Zoetis,Germany) and analgesic (fentanyl, Janssen, Germany) aftercare. By meansof the antennae installed in the animal pen, the blood pressure and ECGsignals are forwarded to a data acquisition computer and evaluated byanalysis software (Ponemah, Data Sciences International, USA). Thetelemetry system makes it possible to continuously monitor bloodpressures and ECG signals in conscious animals. Technical details can befound in the documentation from the manufacturing company (Data SciencesInternational, USA).

The substances to be investigated are administered orally to the healthydogs in suitable solvent mixtures by means of a gelatine capsule. Avehicle-treated group of animals is employed as control. The telemetrymeasurement is started before substance administration and recorded fora time period of several hours. The time course is displayed graphicallyby means of data smoothed by determination of means with the aid of theGraphPadPrism software (GraphPad, USA). To analyse the HRV, the ECG dataare subjected to a frequency-domain heart rate variability analysis. Forthis purpose, the R-R intervals of the recorded ECGs are used. Dataoutside the previously defined range of 0.2 s-1.5 s are excluded fromthe analysis. The excluded data are replaced by values which had beenobtained by linear interpolation. These data are converted by splineinterpolation into equally-spaced supporting points. To analyse theheart rate variability, the data are further subdivided in 30 s steps topackets of 300 s length. For each data packet, a Fourier transformationis calculated. The power is further calculated in three frequency bands(vlf=0.0033-0.04 l/s; lf=0.04-0.15 l/s; hf=0.15-0.5 l/s). Tocharacterize the test substance, the total power (sum total of all threefrequency bands) of the HRV analysis is used.

1: A compound of formula (I)

in which R¹ is NR⁴R⁵, in which R⁴ is hydrogen, methyl, (C₂-C₄)-alkyl or(C₃-C₆)-cycloalkyl, where (C₂-C₄)-alkyl may be substituted by hydroxylor up to trisubstituted by fluorine and R⁵ is (C₁-C₆)-alkyl,(C₃-C₆)-cycloalkyl, 3- to 6-membered saturated heterocyclyl or(C₁-C₄)-alkylsulphonyl, where (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl and 3-to 6-membered saturated heterocyclyl may be up to trisubstituted,identically or differently, by methyl, difluoromethyl, trifluoromethyl,hydroxyl, hydroxycarbonyl, oxo, methoxy, difluoromethoxy,trifluoromethoxy and cyano, and additionally up to tetrasubstituted byfluorine, or R⁴ and R⁵ together with the nitrogen atom to which they arebonded form a saturated or partially unsaturated, 3- to 6-memberedmonocyclic or 6- to 10-membered bicyclic heterocycle which may containone or two further, identical or different heteroatoms from the group ofN, O, S, SO and/or SO₂ as ring members, where the 3- to 6-memberedmonocyclic and the 6- to 10-membered bicyclic heterocycle may each besubstituted by 1 to 5 substituents independently selected from the groupof (C₁-C₄)-alkyl, difluoromethyl, trifluoromethyl, hydroxy,hydroxycarbonyl, oxo, (C₁-C₃)-alkoxy, difluoromethoxy, trifluoromethoxy,cyano, (C₁-C₃)-alkoxycarbonyl, aminocarbonyl,mono-(C₁-C₃)-alkylaminocarbonyloxy, —NHC(═O)R^(22A) and—CH₂NHC(═O)R^(22B), and additionally up to tetrasubstituted by fluorine,in which R^(22A) and R^(22B) independently represent (C₁-C₃)-alkyl orcyclopropyl, and in which (C₁-C₄)-alkyl may be mono- or disubstituted,identically or differently, by hydroxyl and (C₁-C₃)-alkoxy, and up totetrasubstituted by fluorine, R² is a group of the formula

in which * marks the bonding site to the nitrogen atom of the amidemoiety, R^(6A) is hydrogen or (C₁-C₄)-alkyl, R^(6B) is hydrogen,(C₁-C₄)-alkyl, cyclopropyl, trifluoromethyl, methoxymethyl ortrifluoromethoxymethyl, R⁷ is (C₁-C₄)-alkyl, cyclopropyl or cyclobutyl,where (C₁-C₄)-alkyl may be up to pentasubstituted and cyclopropyl andcyclobutyl up to tetrasubstituted by fluorine, Y¹ is —(CH₂)_(k)—, —CF₂—,—O—CH₂—, —CH₂—O— or —CH₂—O—CH₂—, in which k is 0, 1, 2 or 3, R⁸ is up topenta-fluorine-substituted (C₁-C₂)-alkyl or trifluoromethoxymethyl, L¹is a bond or a group of the formula—C(R^(9A)R^(9B))—(C(R^(10A)R^(10B)))_(m)—, in which m represents 0 or 1,R^(9A) represents hydrogen or methyl, R^(9B) represents hydrogen,methyl, trifluoromethyl, pentafluoroethyl or trifluoromethoxymethyl,R^(10A) and R^(10B) independently represent hydrogen or methyl, Ar² isphenyl, where phenyl may be mono- to trisubstituted, identically ordifferently, by fluorine, chlorine, (C₁-C₃)-alkyl,difluoromethoxymethyl, trifluoromethoxymethyl and/or trifluoromethyl, oris a 5- to 10-membered bicyclic or tricyclic carbocycle, where the 5- to10-membered bicyclic or tricyclic carbocycle may be up totrisubstituted, identically or differently, by (C₁-C₃)-alkyl andtrifluoromethyl, and additionally up to tetrasubstituted by fluorine,Ar¹ is a group of the formula

in which ** marks the bonding site to the nitrogen atom, R^(3A) isfluorine, chlorine or trifluoromethyl, R^(3B) is hydrogen or fluorine,and R^(3C) is hydrogen, fluorine or chlorine. and the N-oxides, salts,solvates, salts of the N-oxides and solvates of the N-oxides or saltsthereof. 2: The compound according to claim 1, in which R¹ is NR⁴R⁵, inwhich R⁴ is hydrogen or methyl, and R⁵ is (C₁-C₄)-alkyl ormethylsulphonyl, where (C₁-C₄)-alkyl may be up to disubstituted byhydroxyl and additionally up to trisubstituted by fluorine, or R⁴ and R⁵together with the nitrogen atom to which they are bonded form asaturated or partially unsaturated, 4- to 6-membered monocyclic or 6- to10-membered bicyclic heterocycle which may contain one or two furtherheteroatoms from the group of N, O, S, SO and SO₂ as ring member, wherethe 4- to 6-membered monocyclic and the 6- to 10-membered bicyclicheterocycle may each be substituted by 1 to 5 substituents independentlyselected from the group of (C₁-C₃)-alkyl, difluoromethyl,trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxyl, oxo, methoxy,difluoromethoxy, trifluoromethoxy, methoxymethyl, cyano,methoxycarbonyl, aminocarbonyl and monomethylaminocarbonyloxy, andadditionally up to tetrasubstituted by fluorine, R² is a group of theformula

in which * marks the bonding site to the nitrogen atom of the amidemoiety, R^(6A) is hydrogen or methyl, R^(6B) is hydrogen, (C₁-C₄)-alkyl,cyclopropyl, trifluoromethyl or trifluoromethoxymethyl, R⁷ is(C₁-C₄)-alkyl, cyclopropyl or cyclobutyl, where (C₁-C₄)-alkyl may be upto pentasubstituted by fluorine, Y¹ is —(CH₂)_(k)—, —CF₂—, —O—CH₂—,—CH₂—O— or —CH₂—O—CH₂—, in which k is 0, 1, 2 or 3, R⁸ is methyl,trifluoromethyl or 2,2,2-trifluoroethyl, L¹ is a bond or a group of theformula —CR^(9A)R^(9B)—, in which R^(9A) represents hydrogen or methyl,R^(9B) represents hydrogen, methyl, trifluoromethyl ortrifluoromethoxymethyl, Ar² is phenyl, which may be mono- ordisubstituted, identically or differently, by fluorine, chlorine, methyland/or trifluoromethyl, R¹¹, R¹² and R²³ are each independentlyhydrogen, fluorine, methyl, ethyl or trifluoroethyl, n is the number 1or 2, where, if one of the substituents R¹¹, R¹² or R²³ occurs twice ineach case, its definitions may independently be the same or different,Ar¹ is a group of the formula

in which ** marks the bonding site to the nitrogen atom, R^(3A) isfluorine, chlorine or trifluoromethyl, R^(3B) is hydrogen or fluorineand R^(3C) is hydrogen, fluorine or chlorine and the salts, solvates andsolvates of the salts thereof. 3: The compound according to claim 1, inwhich R¹ is NR⁴R⁵, in which R⁴ is hydrogen or methyl, and R⁵ is methyl,isopropyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl or2-hydroxypropyl, or is a 4- to 6-membered monocyclic or 6- to 8-memberedbicyclic heterocycle which is bonded via a nitrogen atom and is of theformula

in which *** marks the bonding site to the carbon atom of the pyridinering, the ring Q₁ is a group of the formula

in which #¹ and #² mark the bonding site to the carbon atom of thepyrrolidine ring, and Y⁷ is —CF₂— or —CHR¹⁵—, in which R¹⁵ representsmethoxymethyl, and R¹⁶ is hydroxyl, R^(13A) is fluorine, hydroxyl,hydroxymethyl, methyl, trifluoromethyl or methoxy, R^(13D) is hydrogen,fluorine, methyl, hydroxyl, hydroxymethyl, methoxy or difluoromethoxy,R^(13E) is hydrogen, fluorine, methyl, hydroxyl, hydroxymethyl ormethoxy, R^(13F) is fluorine, methyl, hydroxyl, hydroxymethyl or cyano,R^(13G) is fluorine or hydroxyl, R^(13H) is hydrogen, methyl,hydroxymethyl, aminocarbonyl or methoxycarbonyl, R^(13J) is oxo,hydroxymethyl or difluoromethyl, R^(13K) is hydrogen, methyl or2-hydroxyethyl, R^(13L) is hydrogen or methyl, R^(13M) is ethyl,2-hydroxyethyl or cyano, R^(13N) is hydrogen or ethyl, R^(13O) ishydrogen or hydroxyl, R¹⁴ is methyl, methoxycarbonyl or aminocarbonyl, qis the number 0, 1 or 2, r is the number 0, 1, 2 or 3, s is the number 0or 1, t is the number 0, 1, 2, 3 or 4, where, in the case that thesubstituents R^(13A), R^(13D), R^(13E), R^(13F), R^(13G), R^(13J) andR^(13L) occur more than once, the definitions thereof may each be thesame or different, R² is a group of the formula

in which * marks the bonding site to the nitrogen atom of the amidemoiety, R^(6A) is hydrogen or methyl, R^(6B) is methyl, ethyl,cyclopropyl, trifluoromethyl or trifluoromethoxymethyl, R⁷ is methyl,ethyl, n-propyl, isopropyl, tert-butyl, 2-methylprop-1-yl,trifluoromethyl, difluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethylor cyclopropyl, R⁸ is 2,2,2-trifluoroethyl, L¹ is a bond or a group ofthe formula —CR^(9A)R^(9B)—, in which R^(9A) represents hydrogen ormethyl, R^(9B) represents hydrogen, methyl, trifluoromethyl ortrifluoromethoxymethyl, Ar² is phenyl, which may be mono- ordisubstituted, identically or differently, by fluorine, chlorine, methyland/or trifluoromethyl, R¹¹ is hydrogen, fluorine or methyl, R^(12A) ishydrogen, fluorine, methyl, ethyl or trifluoromethyl, R^(12B) ishydrogen or fluorine, R²³ is hydrogen, fluorine or trifluoromethyl, andAr¹ is a group of the formula

in which ** marks the bonding site to the nitrogen atom, R^(3A) isfluorine or chlorine, R^(3B) is hydrogen or fluorine, and R^(3C) ishydrogen, fluorine or chlorine and the salts, solvates and solvates ofthe salts thereof. 4: The compound according to claim 1, in which R¹ isa group of the formula

in which *** marks the bonding site to the carbon atom of the pyridinering, R^(13DA) is hydrogen or methyl, R^(13EA) is hydroxyl orhydroxymethyl, R^(13EB) is methyl or hydroxymethyl, R^(13EC) is hydrogenor methyl, R^(13LA) is hydrogen or methyl, R² is a group of the formula

in which * marks the bonding site to the nitrogen atom of the amidemoiety, R^(6B) is trifluoromethoxymethyl, R^(7A) is methyl, ethyl,trifluoromethyl or cyclopropyl, R^(7B) is trifluoromethyl,difluoromethyl or 2,2,2-trifluoroethyl, R^(7C) is methyl or ethyl, R¹⁹is chlorine, and Ar¹ is a group of the formula

in which ** marks the bonding site to the nitrogen atom, R^(3A) isfluorine or chlorine, and R^(3C) is hydrogen or fluorine, and the salts,solvates and solvates of the salts thereof. 5: The compound according toclaim 1, in which R¹ is a group of the formula

in which * ** marks the bonding site to the carbon atom of the pyridinering, R² is a group of the formula

in which * marks the bonding site to the nitrogen atom of the amidemoiety, R^(7A) is ethyl, trifluoromethyl or cyclopropyl, R^(7B) istrifluoromethyl, R^(7C) is methyl or ethyl, and Ar¹ is a group of theformula

in which ** marks the bonding site to the nitrogen atom, and the salts,solvates and solvates of the salts thereof. 6: A process for preparing acompound of formula (I) according to claim 1, wherein [A] a compound ofthe formula (II)

in which R² and Ar¹ are as defined in claim 1, and Hal is fluorine,chlorine, bromine or iodine, is reacted with a compound of the formula(III)R¹—H  (III) in which R¹ is as defined in claim 1, to give thecarboxamide of the formula (I)

in which R¹, R² and Ar¹ are as defined in claim 1, or [B] a compound ofthe formula (IV)

in which R¹ and Ar¹ are as defined in claim 1, is reacted with acompound of the formula (V)R²—NH₂  (V) in which R² is as defined in claim 1, to give the compoundof the formula (I)

in which R¹, R² and Ar¹ are as defined in claim 1, and wherein thecompound of formula (I) is optionally separated into enantiomers and/ordiastereomers and/or converted with the appropriate (i) solvents and/or(ii) bases or acids to their solvates, salts and/or solvates of thesalts. 7: A compound of formula (II)

R² is a group of the formula

in which * marks the bonding site to the nitrogen atom of the amidemoiety, R^(6A) is hydrogen or (C₁-C₄)-alkyl, R^(6B) is hydrogen,(C₁-C₄)-alkyl, cyclopropyl, trifluoromethyl, methoxymethyl ortrifluoromethoxymethyl, R⁷ is (C₁-C₄)-alkyl, cyclopropyl or cyclobutyl,where (C₁-C₄)-alkyl may be up to pentasubstituted and cyclopropyl andcyclobutyl up to tetrasubstituted by fluorine, Y¹ is —(CH₂)_(k)—, —CF₂—,—O—CH₂—, —CH₂—O— or —CH₂—O—CH₂—, in which k is 0, 1, 2 or 3, R⁸ is up topenta-fluorine-substituted (C₁-C₂)-alkyl or trifluoromethoxymethyl, L¹is a bond or a group of the formula—C(R^(9A)R^(9B))—(C(R^(10A)R^(10B)))_(m)—, in which m represents 0 or 1,R^(9A) represents hydrogen or methyl, R^(9B) represents hydrogen,methyl, trifluoromethyl, pentafluoroethyl or trifluoromethoxymethyl,R^(10A) and R^(10B) independently represent hydrogen or methyl, Ar² isphenyl, where phenyl may be mono- to trisubstituted, identically ordifferently, by fluorine, chlorine, (C₁-C₃)-alkyl,difluoromethoxymethyl, trifluoromethoxymethyl and/or trifluoromethyl, oris a 5- to 10-membered bicyclic or tricyclic carbocycle, where the 5- to10-membered bicyclic or tricyclic carbocycle may be up totrisubstituted, identically or differently, by (C₁-C₃)-alkyl andtrifluoromethyl, and additionally up to tetrasubstituted by fluorine,Ar¹ is a group of the formula

in which ** marks the bonding site to the nitrogen atom, R^(3A) isfluorine, chlorine or trifluoromethyl, R^(3B) is hydrogen or fluorine,and R^(3C) is hydrogen, fluorine or chlorine, and Hal is fluorine,chlorine, bromine or iodine. 8: A compound of formula (IV)

in which R¹ is NR⁴R⁵, in which R⁴ is hydrogen, methyl, (C₂-C₄)-alkyl or(C₃-C₆)-cycloalkyl, where (C₂-C₄)-alkyl may be substituted by hydroxylor up to trisubstituted by fluorine and R⁵ is (C₁-C₆)-alkyl,(C₃-C₆)-cycloalkyl, 3- to 6-membered saturated heterocyclyl or(C₁-C₄)-alkylsulphonyl, where (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl and 3-to 6-membered saturated heterocyclyl may be up to trisubstituted,identically or differently, by methyl, difluoromethyl, trifluoromethyl,hydroxyl, hydroxycarbonyl, oxo, methoxy, difluoromethoxy,trifluoromethoxy and cyano, and additionally up to tetrasubstituted byfluorine, or R⁴ and R⁵ together with the nitrogen atom to which they arebonded form a saturated or partially unsaturated, 3- to 6-memberedmonocyclic or 6- to 10-membered bicyclic heterocycle which may containone or two further, identical or different heteroatoms from the group ofN, O, S, SO and/or SO₂ as ring members, where the 3- to 6-memberedmonocyclic and the 6- to 10-membered bicyclic heterocycle may each besubstituted by 1 to 5 substituents independently selected from the groupof (C₁-C₄)-alkyl, difluoromethyl, trifluoromethyl, hydroxy,hydroxycarbonyl, oxo, (C₁-C₃)-alkoxy, difluoromethoxy, trifluoromethoxy,cyano, (C₁-C₃)-alkoxycarbonyl, aminocarbonyl,mono-(C₁-C₃)-alkylaminocarbonyloxy, —NHC(═O)R^(22A) and—CH₂NHC(═O)R^(22B), and additionally up to tetrasubstituted by fluorine,in which R^(22A) and R^(22B) independently represent (C₁-C₃)-alkyl orcyclopropyl, and in which (C₁-C₄)-alkyl may be mono- or disubstituted,identically or differently, by hydroxyl and (C₁-C₃)-alkoxy, and up totetrasubstituted by fluorine, and Ar¹ is a group of the formula

in which ** marks the bonding site to the nitrogen atom, R^(3A) isfluorine, chlorine or trifluoromethyl, R^(3B) is hydrogen or fluorine,and R^(3C) is hydrogen, fluorine or chlorine.
 9. (canceled) 10: A methodfor treatment and/or prophylaxis of diseases, comprising administeringto a patient in need thereof a compound according to claim
 1. 11: Amethod for treatment and/or prophylaxis of heart failure, coronary heartdisease, atrial and ventricular arrhythmia, renal failure andnephropathy, comprising administering to a patient in need thereof acompound according to claim
 1. 12: A pharmaceutical combinationcomprising a compound according to claim 1 in combination with one ormore further active ingredients selected from the group consisting ofactive hypotensive ingredients, active antiarrhythmic ingredients,vasopressin receptor antagonists, PDE 5 inhibitors, platelet aggregationinhibitors, sGC activators and sGC stimulators. 13: A pharmaceuticalcomposition comprising a compound according to claim 1 in combinationwith an inert, non-toxic, pharmaceutically suitable excipient. 14: Amethod for treatment and/or prophylaxis of heart failure, coronary heartdisease, atrial and ventricular arrhythmia, renal failure andnephropathy, comprising administering to a patient in need thereof apharmaceutical combination according to claim
 12. 15. (canceled) 16: Amethod for treatment and/or prophylaxis of cardiovascular disordersand/or renal disorders, comprising administering a positive allostericmodulator of the muscarinic M2 receptor to a patient in need thereof.17: The method of claim 16, wherein the positive allosteric modulator ofthe muscarinic M2 receptor has subtype selectivity for the M2 receptorover the various muscarinic acetylcholine receptors in terms of thepositive allosteric effect. 18: The method of claim 16, wherein thepositive allosteric modulator of the muscarinic M2 receptor has, withina concentration range of 1 μM-10 μM, an identical or higher selectivityfor the muscarinic M2 receptor than for the muscarinic M4 receptor, andwherein the selectivity is determined as the quotient of the respectivemodulator-related allosteric shift in the EC₅₀ value of the AChdose-response curve for the M2 receptor relative to the M4 receptor. 19:The method of claim 16, wherein the positive allosteric modulator of themuscarinic M2 receptor has, within a concentration range of 5 μM-20 μM,a selectivity at least 4 times higher for the muscarinic M2 receptorthan for the muscarinic M1 receptor, and wherein the selectivity isdetermined as the quotient of the respective modulator-relatedallosteric shift in the EC₅₀ value of the ACh dose-response curve forthe M2 receptor relative to the M1 receptor. 20: The method of claim 16,wherein the positive allosteric modulator of the muscarinic M2 receptorcomprises a 1-arylnaphthyridine-3-carboxamide structure. 21: A methodfor treatment and/or prophylaxis of heart failure, coronary heartdisease, atrial and ventricular arrhythmia, renal failure andnephropathy, comprising administering a pharmaceutical compositionaccording to claim 13 to a patient in need thereof.